Guanidine mimics as factor Xa inhibitors

ABSTRACT

The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula I: 
                         
or pharmaceutically acceptable salt forms thereof, wherein rings D-E represent guanidine mimics, which are useful as inhibitors of factor Xa.

This application is a continuation of Ser. No. 10/098,994 filed on Mar.13. 2002, now U.S. Pat. No. 6,958,356 which is a continuation of U.S.application Ser. No. 09/924,381 filed on Aug. 8, 2001, now U.S. Pat. No.6,906,070, which is a divisional application of U.S. application Ser.No. 09/099,358 filed on Jun. 18, 1998 and issued as U.S. Pat. No.6,339,099 on Jan. 15, 2002, which claims the benefit of U.S. ProvisionalApplication No. 60/050,265 filed on Jun. 20, 1997, the contents of whichare hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates generally to novel guanidine mimics which areinhibitors of trypsin-like serine protease enzymes, especially factorXa, pharmaceutical compositions containing the same, and methods ofusing the same as anticoagulant agents for treatment and prevention ofthromboembolic disorders.

BACKGROUND OF THE INVENTION

WO 96/28427 describes benzamidine anticoagulants of the formula:

wherein Z¹ and Z² are O, N(R), S or OCH₂ and the central ring may bephenyl or a variety of heterocycles. The presently claimed compounds donot contain the Z¹ linker or the substitution pattern of the abovecompounds.

WO 95/13155 and PCT International Application US 96/07692 describeisoxazoline and isoxazole fibrinogen receptor antagonists of theformula:

wherein R¹ may be a basic group, U—V may be a six-membered aromaticring, W—X may be a variety of linear or cyclic groups, and Y is an oxygroup. Thus, these compounds all contain an acid functionality (i.e.,W—X—C(═O)—Y). In contrast, the presently claimed compounds do notcontain such an acid functionality.

EP 0,513,387 depicts active oxygen inhibitors which are oxazoles orthiazoles of the formula:

wherein X is O or S, R² is preferably hydrogen, and both R¹ and R³ aresubstituted cyclic groups, with at least one being phenyl. The presentlyclaimed invention does not relate to these types of oxazoles orthiazoles.

WO 95/18111 addresses fibrinogen receptor antagonists, containing basicand acidic termini, of the formula:

wherein R¹ represents the basic termini, U is an alkylene or heteroatomlinker, V may be a heterocycle, and the right hand portion of themolecule represents the acidic termini. The presently claimed compoundsdo not contain the acidic termini of WO 95/18111.

In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregationinhibitors which are 5-membered heterocycles of the formula:

wherein the heterocycle may be aromatic and groups A-B-C- and F-E-D- areattached to the ring system. A-B-C- can be a wide variety ofsubstituents including a basic group attached to an aromatic ring. TheF-E-D- group, however, would appear to be an acidic functionality whichdiffers from the present invention. Furthermore, use of these compoundsas inhibitors of factor Xa is not discussed.

Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT₁ agonists whichare indole substituted five-membered heteroaromatic compounds of theformula:

wherein R¹ may be pyrrolidine or piperidine and A may be a basic groupincluding amino and amidino. Baker et al, however, do not indicate thatA can be a substituted ring system like that contained in the presentlyclaimed heteroaromatics.

Baker et al, in WO 94/02477, discuss 5-HT₁ agonists which areimidazoles, triazoles, or tetrazoles of the formula:

wherein R¹ represents a nitrogen containing ring system or a nitrogensubstituted cyclobutane, and A may be a basic group including amino andamidino. But, Baker et al do not indicate that A can be a substitutedring system like that contained in the presently claimedheteroaromatics.

Tidwell et al, in J. Med. Chem. 1978, 21(7), 613–623, describe a seriesof diarylamidine derivatives including3,5-bis(4-amidinophenyl)isoxazole. This series of compounds was testedagainst thrombin, trypsin, and pancreatic kallikrein. The presentlyclaimed invention does not include these types of compounds.

Activated factor Xa, whose major practical role is the generation ofthrombin by the limited proteolysis of prothrombin, holds a centralposition that links the intrinsic and extrinsic activation mechanisms inthe final common pathway of blood coagulation. The generation ofthrombin, the final serine protease in the pathway to generate a fibrinclot, from its precursor is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it iscalculated that one molecule of factor Xa can generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for thecatalytic effect of the factor IXa-factor VIII Complex: Probable role ofthe complex in the amplification of blood coagulation. Thromb. Res.1979, 15, 617–629), inhibition of factor Xa may be more efficient thaninactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are neededas potentially valuable therapeutic agents for the treatment ofthromboembolic disorders. It is thus desirable to discover new factor Xainhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelguanidine mimics which are useful as factor Xa inhibitors orpharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating thromboembolic disorders comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, wherein D,E, and M are defined below, are effective factor Xa inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides novelcompounds of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

-   ring D is a 5 membered aromatic system containing from 1–2    heteroatoms selected from the group N, O, and S;-   ring D is substituted with 0–2 R;-   ring E contains 0–2 N atom and is substituted by 0–1 R;-   R is selected from Cl, F, Br, I, OH, C₁₋₃ alkoxy, NH₂, NH(C₁₋₃    alkyl), N(C₁₋₃ alkyl)₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃    alkyl)₂, CH₂CH₂NH₂, CH₂CH₂NH(C₁₋₃ alkyl), and CH₂CH₂N(C₁₋₃ alkyl)₂;-   M is

-   Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r)O(CH₂)_(r),    (CH₂)_(r)NR³(CH₂)_(r), (CH₂)_(r)C(O) (CH₂)_(r),    (CH₂)_(r)C(O)O(CH₂)_(r), (CH₂)_(r)OC(O) (CH₂)_(r),    (CH₂)_(r)C(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O) (CH₂)_(r),    (CH₂)_(r)OC(O)O(CH₂)_(r), (CH₂)_(r)OC(O)NR³(CH₂)_(r),    (CH₂)_(r)NR³C(O)O(CH₂)_(r), (CH₂)_(r)NR³C(O)NR³(CH₂)_(r),    (CH₂)_(r)S(O)_(p)(CH₂)_(r), (CH₂)_(r)SO₂NR³(CH₂)_(r),    (CH₂)_(r)NR³SO₂(CH₂)_(r), and (CH₂)_(r)NR³SO₂NR³(CH₂)_(r), provided    that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond    with ring M or group A;-   R^(1a) and R^(1b) are independently H or selected from    —(CH₂)_(r)—R^(1′), —CH═CH—R^(1′), NHCH₂R^(1″), OCH₂R^(1″),    SCH₂R^(1″), NH(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), and    S(CH₂)₂(CH₂)_(t)R^(1″),-   R^(1′) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO,    (CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R²,    (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR²,    C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b),    NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a),    C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocyclic    group substituted with 0–2 R⁴, and 5–10 membered heterocyclic system    containing from 1–4 heteroatoms selected from the group consisting    of N, O, and S substituted with 0–2 R⁴, provided that if R^(1′) is    substituted with R⁴ then R⁴ is other than NH(CH₂)₂(CH₂)_(t)R^(1′),    O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′);-   R^(1″) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),    S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);-   R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,    C₃₋₆ carbocyclic group substituted with 0–2 R^(4b), and 5–6 membered    heterocyclic system containing from 1–4 heteroatoms selected from    the group consisting of N, O, and S substituted with 0–2 R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl,    benzyl, phenethyl, C₃₋₆ carbocyclic group substituted with 0–2    R^(4b), and 5–6 membered heterocyclic system containing from 1–4    heteroatoms selected from the group consisting of N, O, and S    substituted with 0–2 R^(4b);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆    alkyl, benzyl, C₃₋₆ carbocyclic group substituted with 0–2 R^(4b),    and 5–6 membered heterocyclic system containing from 1–4 heteroatoms    selected from the group consisting of N, O, and S substituted with    0–2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy,    C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic group substituted with 0–2    R^(4b), and 5–6 membered heterocyclic system containing from 1–4    heteroatoms selected from the group consisting of N, O, and S    substituted with 0–2 R^(4b);-   R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;-   R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and    phenyl;-   R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, and phenyl;-   A is C₃₋₁₀ carbocyclic group substituted with 0–2 R⁴;-   B is Y;-   Y is 5–10 membered heterocyclic system containing from 1–4    heteroatoms selected from the group consisting of N, O, and S    substituted with 0–2 R^(4a);-   R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl,    Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a),    (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a),    C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²) NR²R^(2a),    C(O)NHC (═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄    alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NHCH₂R^(1″),    OCH₂R^(1″)SCH₂R^(1″), NH(CH₂)₂(CH₂)_(t)R^(1′),    O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′),-   R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,    (CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, I, C₁₋₄ alkyl, —CN, NO₂,    (CH₂)_(r)NR²R^(2a), (CH₂)_(r)NR²R^(2b), (CH₂)_(r)C(O)R^(2c),    NR²C(O)R^(2b), C(O)NR²R^(2a), C(O)NH(CH₂)₂NR²R^(2a),    NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a),    SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄    alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃;-   R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F,    Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a),    (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),    NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a),    SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃,    NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl,    and (CF₂)_(r)CF₃;-   R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl    substituted with 0–2 R⁶, and benzyl substituted with 0–2 R⁶;-   R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², F, Cl,    Br, I, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b),    NR₂C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂,    SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl;-   p is selected from 0, 1, and 2;-   r is selected from 0, 1, 2, and 3; and,-   t is selected from 0 and 1.

[2] In another embodiment, the present invention provides novelcompounds, wherein:

-   M is

[3] In another embodiment, the present invention provides novelcompounds, wherein;

-   D-E is selected from the group:    -   3-aminoindazol-5-yl; 3-hydroxyindazol-5-yl;        3-aminobenzisoxazol-5-yl; 3-hydroxybenzisoxazol-5-yl;        3-aminobenzisothiazol-5-yl; 3-hydroxybenzisothiazol-5-yl; and,        1-aminoisoindol-6-yl.

[4] In another embodiment, the present invention provides novelcompounds, wherein;

-   D-E is selected from the group:    -   3-aminobenzisoxazol-5-yl; 3-aminobenzisothiazol-5-yl; and,        1-aminoisoindol-6-yl.

[5] In another embodiment, the present invention provides novelcompounds wherein:

-   D-E is selected from the group:    -   3-aminobenzisoxazol-5-yl and 1-aminoisoindol-6-yl.

[6] In another embodiment, the present invention provides novelcompounds wherein:

-   D-E is 3-aminobenzisoxazol-5-yl.

[7] In another embodiment, the present invention provides novelcompounds wherein:

-   Z is selected from (CH₂)_(r)C(O) (CH₂)_(r), (CH₂)_(r)C(O)O(CH₂)_(r),    (CH₂)_(r)C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r), and    (CH₂)_(r)SO₂NR³(CH₂)_(r).

[8] In another embodiment, the present invention provides novelcompounds wherein:

-   Z is selected from (CH₂)_(r)C(O) (CH₂)_(r) and    (CH₂)_(r)C(O)NR³(CH₂)_(r).

[9] In another embodiment, the present invention provides novelcompounds wherein:

-   Z is (CH₂)_(r)C(O)NR³(CH₂)_(r).

[10] In another embodiment, the present invention provides novelcompounds wherein:

-   Z is C(O)NH.

[11] In another embodiment, the present invention provides novelcompounds wherein:

-   Y is selected from one of the following carbocyclic and heterocyclic    systems which are substituted with 0–2 R^(4a);    -   phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,        morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,        oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole,        1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole,        1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole,        1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole,        1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran,        indole, benzimidazole, benzoxazole, benzthiazole, indazole,        benzisoxazole, benzisothiazole, and isoindazole.

[12] In another embodiment, the present invention provides novelcompounds wherein:

-   Y is selected from one of the following carbocyclic and heterocyclic    systems which are substituted with 0–2 R^(4a);    -   phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,        morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,        benzimidazolyl, oxadiazole, thiadiazole, triazole,        1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole,        1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,        1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole,        1,2,4-triazole, 1,2,5-triazole, and 1,3,4-triazole.

[13] In another embodiment, the present invention provides novelcompounds wherein:

-   Y is imidazolyl substituted with 0–2 R^(4a).

[14] In another embodiment, the present invention provides novelcompounds wherein:

-   A is C₅₋₆ carbocyclic group substituted with 0–2 R⁴; and,-   R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl,    C₁₋₄ alkyl, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2c), CH₂C(O)R^(2c),    C(O)NR²R^(2a), C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a),    SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, S(O)₂R⁵, and CF₃.

[15] In another embodiment, the present invention provides novelcompounds wherein:

-   A is phenyl substituted with R⁴; and,-   R⁴ is F.

[16] In another embodiment, the present invention provides novelcompounds wherein:

-   R^(1a) is —(CH₂)_(r)—R^(1′); and,-   R^(1′) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, CF₃,    (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), S(O)_(p)R^(2b), and    NR²SO₂R^(2b).

[17] In another embodiment, the present invention provides novelcompounds wherein:

-   R^(1a) is selected from H, C₁₋₃ alkyl, F, Cl, Br, CF₃, CH₂OR²,    C(O)R^(2c), S(O)_(p)R^(2b), and NR²SO₂R^(2b).

[18] In another embodiment, the present invention provides novelcompounds wherein:

-   R^(1a) is CF₃.

[19] In another embodiment, the present invention provides novelcompounds wherein:

-   R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F,    Cl, C₁₋₄ alkyl, NR²R^(2a), CH₂NR²R^(2a), NR²R^(2b), CH₂NR²R^(2b),    (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),    C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)₂R⁵, and    CF₃.

[20] In another embodiment, the present invention provides novelcompounds wherein:

-   R^(4a), at each occurrence, is selected from CH₂OR² and    CH₂NR²R^(2a).

[21] In another embodiment, the present invention provides novelcompounds wherein:

-   R², at each occurrence, is selected from H and C₁₋₆ alkyl;-   R^(2a), at each occurrence, is selected from H and C₁₋₆ alkyl;-   R^(2b), at each occurrence, is selected from C₁₋₄ alkoxy and C₁₋₆    alkyl; and,-   R^(2c), at each occurrence, is selected from OH, C₁₋₄ alkoxy, and    C₁₋₆ alkyl.

[22] In another embodiment, the present invention provides novelcompounds wherein:

-   R², at each occurrence, is selected from H and CH₃; and,-   R^(2a), at each occurrence, is selected from H and CH₃.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt form thereof.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0–2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₆ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl; “Alkenyl” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain, such as ethenyl, propenyl, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to13-membered bicyclic or tricyclic, any of which may be saturated,partially unsaturated, or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and from 1 to 4 heteroatoms independently selected from the groupconsisting of N, O and S and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. As used herein, the term “aromatic heterocyclic system”is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or7- to 10-membered bicyclic heterocyclic aromatic ring which consists ofcarbon atoms and from 1 to 4 heterotams independently selected from thegroup consisting of N, O and S. It is preferred that the total number ofS and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothlofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.Preferred heterocycles include, but are not limited to, pyridinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl,indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also includedare fused ring and spiro compounds containing, for example, the aboveheterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formula (I), and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

One general synthesis of compounds of Formula I where ring M is N-linkedis shown in Scheme 1a. Q, B′ and R^(f) are protected functional groupsthat can be converted to R, B and R^(1a) respectively. D-E can also becalled P1, the sidechain that fits into the S1 pocket of fXa. Thecompounds can also be obtained by changing the sequences of the reactionsteps as described in Scheme 1a. For N-linked M ring, the appropriateheterocyclic aniline is treated under conditions described in “TheChemistry of Heterocyclic Compounds, Weissberger, A. and Taylor, E. C.Ed., John Wiley & Sons” or as described later in the synthesis sectionto give N-linked ring M. Further modifications and deprotections giveN-linked ring M with R, Z-A-B and R^(1a) substitutents.

In Scheme 1b is shown how to obtain compounds wherein ring M is C-linkedand is either five- or six-membered. The aniline from Scheme 1a isdiazotized with nitrous acid and treated with NaBr to give theheterocyclic bromide. Treatment with n-BuLi followed by DMF gives analdehyde which can be converted to ring M as described in “The Chemistryof Heterocyclic Compounds, Weissberger, A. and Taylor, E. C. Ed., JohnWiley & Sons” or as will be described. Other precursor functional groupslike acid, cyanide, methylketone, etc. can also be used to form the ringM. Further modifications and deprotections can yield five-membered ringM substituted with R, Z-A-B and R^(1a). The corresponding C-linkedsix-membered ring M can be obtained by converting the above bromide withn-butyl lithium and triisopropyl borate to give the heterocylic boronicacid. Suzuki coupling with the appropriate heterocyclic bromide,followed by modifications and deprotections gives the C-linkedsix-membered ring M with R, Z-A-B and R^(1a) substitutents.

Scheme 2a shows the synthesis of 2-aminoisoquinoline P1 in which thegroups R^(1a) and Z-A-B are attached to the pyrazole C-3 and C-5respectively. Synthesis begins with 7-aminoisoquinoline (J. Chem. Soc.1951, 2851). Diazotization and reduction with stannous chloride convertsthe aryl amine to a hydrazine (J. Org. Chem. 1956, 21, 394) whichcondenses with a R^(1a) and Z-H substituted keto-oximes to furnishpyrazoles with high regioselectivity (J. Heterocycl. Chem. 1993, 30,307). Coupling of the resultant Z-H substituted pyrazoles with fragmentA-B′ is accomplished using standard procedures for Z as a carboxylic,amino or sulfonic moiety. For Z as a carboxylate the coupling isaccomplished using Weinreb's procedure (Tetr. Lett. 1977, 48, 4171) withprimary amines of the type H₂N-A-B′. 1-Amination of the isoquinoline isaccomplished via formation of the N-oxide followed by treatment withtosyl chloride and then ethanolamine (U.S. Pat. No. 4,673,676).Alternatively, the amination transformation may be accomplished viatreatment of the isoquinoline N-oxides with phosphoryl chloride.Subsequent displacement of the resultant 1-chloro substituent is donewith appropriate reagents. Deprotection of groups on fragment Z-A-B′gives final product.

In Scheme 2b is illustrated the preparation of 5-amino substituted1,6-naphthrydine compounds. Compounds of this type can be prepared from3-nitro-1,6-naphthrydine (Tetr. 1989, 45, 2693). Reduction to thecorresponding amine will allow for transformation to the desired5-membered nitrogen containing heterocycle with R^(f) and Z-Hsubstitution. Introduction of a 5-amino moiety may be accomplishedthrough the 5-chloro compound (Chem. Pharm. Bull. 1969, 17, 1045) aspreviously described in Scheme 2a. Suitable protection of the aminosubstituent is employed before introduction of fragment A-B′. Conversionto the final product may be accomplished in an analogous fashion to thatdescribed in Scheme 2a.

In Scheme 2c is shown how to prepare isoquinolines, which contain a1,5-diamine substituent, from 7-aminoisoquinoline by suitable protectionof the amine as an amide, directed nitration, and deprotection of theamine a 5-nitro-7-aminoisoquinoline may be obtained. The desired5-membered nitrogen containing heterocycle with R^(f) and Z-Hsubstitution may be synthesized as previously shown in Scheme 2a. Theaddition of fragment A-B′ and the 1-aminoisoquinoline portion would beaccomplished as described earlier. The transformation of A-B′, R^(f),and the 4-nitro substituent to A-B, R^(1a), and a 4-amino group,respectively, is accomplished by previously outlined methods.

In Scheme 2d is shown how to prepare isoquinolines which contain1,4-diamine substitution. From 7-aminoisoquinoline, the desired5-membered nitrogen containing heterocycle with R^(f) and Z-Hsubstitution may be synthesized as previously shown in Scheme 2a.Nitration to the isoquinoline 4 position may be accomplished usingstandard conditions to afford a 4-nitro moiety. The addition of fragmentA-B′ and the 1-aminoisoquinoline portion can be accomplished asdescribed earlier. The transformation of A-B′, R^(f), and the 4-nitrosubstituent to A-B, R^(1a), and a 4-amino group, respectively, isaccomplished by previously outlined methods.

Scheme 3 illustrates the preparation of an intermediate for3-aminobenzisoxazole and 3-aminoindazole. Compounds of this general typecan be obtained from a fluorocyanobenzaldehyde prepared fromcommercially available 2-fluoro-5-methylbenzonitrile by firstbis-bromination in a nonprotic solvent in the presence of AIBN or othersuitable free radical initiator at a temperature ranging from ambienttemperature to the reflux temperature of the selected solvent or under aUV light. The bis-bromo compound may then be converted to an aldehydeusing a protic solvent in strong acidic or basic conditions at ambienttemperature or higher. The aldehyde or the acid equivalent can then beconverted to various C-linked ring M by methods which will be describedlater.

Scheme 4 outlines the formation of C-linked aminobenzisoxazoles. Theaminobenzisoxazole P1 can be obtained by first treating the oxime ofacetone with potassium t-butoxide in an aprotic polar solvent, followedby the addition of the fluorocyanophenylheterocycle H and then treatmentwith a protic solvent under strongly acidic conditions (J. Heterocycl.chem. 1989, 26, 1293). Coupling and deprotection as described previouslygives 3-aminobenzisoxazoles of Formula I.

Scheme 5 outlines the formation of the C-linked 3-aminoindazoles ofFormula I. Protection of the aldehyde as propylene ketal by standardconditions followed by refluxing with hydrazine in ethanol gives3-aminoindazole ketal. Protection of the amino group with CBZCl anddeprotection of the ketal with HCl/MeOH gives the aldehyde. The aldehydeor the acid equivalent can be converted to various C-linked heterocyclesas described later. Coupling and deprotection as described previouslygives 3-aminoindazoles of Formula I.

Scheme 6 illustrates the preparation of aminobenzimidazole aldehydewhich can be carried onto the C-linked or N-linked heterocycles by themethods described later in the synthesis section. Cyclization of3,4-diaminobenzoate to give cbz-protected 2-aminobenzimidazole followedby DIBAL reduction and oxidation gives the desired aldehyde.

Scheme 7 illustrates the preparation of N-linked aminobenzisoxazoles,aminoindazoles, diaminoquinazolines and aminoquinazolines of Formula I.Compounds of this type can be made from the aniline derivative preparedfrom commercially available 2-fluoro-5-nitrobenzonitrile using tin(II)chloride or other compatible reducing agents in a protic or an aproticsolvent with or without a miscible co-solvent at from ambienttemperature to reflux temperature of the selected solvent

The N-linked 3-aminobenzisoxazoles and 3-aminoindazoles can be obtainedas described previously. The N-linked aminoquinazoline anddiaminoquinazoline P1's can be obtained by condensing the fluorocyanocompound with formamidine acetate or guanidine hydrochloride (J.Heterocycl. Chem. 1988, 25, 1173).

Scheme 8 illustrates the preparation of 1-amino-2-benzopyrazine P1heterocyclic intermediates leading to compounds of Formula I. Compoundsof this general type can be obtained from an aminostilbene prepared fromcommercially available 2-cyano-4-nitrotoluene by first condensing thenitrotoluene with benzaldehyde or one of its analogs in an alcoholicsolvent in the presence of an alkoxide base at a temperature rangingfrom −10° C. to the reflux temperature of the selected solvent. TheNitrostilbene may then be reduced to aminostilbene by reaction withtin(II) chloride or another compatible reducing agent in a proticsolvent with or without a miscible co-solvent at ambient temperature orhigher. The aniline may then be carried on to the N-linked or C-linkedheterocycles H by the methods previously described.

Scheme 8 also further outlines transformation of the N-linked andC-linked (not shown) heterocyclic stilbenes to give 1-aminophthalazinesof Formula I. Oxidative cleavage of the stilbene double bond accordingto the method of Narasimhan et al (Synth. Commun 1985, 15(9), 769) orSheu et al (J. Am Chem. Soc. 1990, 112, 879) or their equivalent shouldgive an aldehyde. The aldehyde can be treated with hydrazine neat or ina polar or apolar solvent at ambient temperature or up to the refluxtemperature of the solvent selected to cause ring closure. Group Z-H canthen be coupled with group H₂N-A-B according to the methods outlined inScheme 2a.

The N-linked and C-linked heterocyclic 2-cyanobenzaldehydes prepared inScheme 8 can also be used as convenient starting materials for thepreparation of N-linked 1,3-diaminoisoquinoline intermediate of Scheme 9and C-linked (not shown) 1,3-diaminoisoquinoline intermediate of Scheme9 by appropriate adaptation of the chemistry outlined below. The2-cyanobenzaldehyde can be reduced to the benzylic alcohol by a hydridereducing agent, preferably sodium borohydride, then treated with asulfonylchloride, methane sulfonyl chloride as suggested by Scheme 9 oran equivalent, using a trialkylamine base and a dry chlorocarbon solventwith cooling. The mesylate and biscyano intermediates can also beconverted to the corresponding 1-aminoisoindole P1 and1-amino-3,4-dihydroisoqunoline P1 respectively.

Scheme 10 illustrates another approach to preparing the N-linked andC-linked heterocyclic benzylic alcohols intermediates. These compoundsmay be obtained from 2-cyano-4-nitro-toluene by photochemical benzylicbromination with N-bromosuccinimide in carbon tetrachloride with a sunlamp and at reflux in the presence of a catalytic amount of a radicalinitiator such as AIBN or dibenzoylperoxide. The benzylic bromide isthen readily displaced with potassium acetate under phase transferconditions using 18-crown-6 as the phase transfer agent along with waterand a non-miscible organic co-solvent with or without heating. Theresulting acetate is then hydrolyzed with aqueous acid or bytransesterification with anhydrous acid in an alcoholic solvent to givea benzylic alcohol. Depending upon the further demands of the chemistryinvolved in heterocycle formation step(s) the benzylic alcohol may beprotected according to the methodology recommended by Greene and Wuts.The nitro group of the resulting product can then be reduced to theaniline according to the methods outlined above for Scheme 8 and thencarried on to N-linked and C-linked heterocyclic benzylic alcohols ofScheme 10. It should be recognized that these benzylic alcohols can bereadily transformed into the benzylic sulfonate ester intermediates ofScheme 9 or oxidized to the benzaldehyde of Scheme 8 by methods known tothe skilled practitioner.

The compounds of the present invention in which the D-E residue isisoquinazolin-1-one can be prepared as described in Scheme 11. Forcompounds which are N-linked to heterocycle M, the reaction of5-nitroisatoic anhydride with formamide at 150° C. affords7-nitroisoquinazolin-1-one which can be reduced to the corresponding7-aminoisoquinazolin-1-one by a variety of reducing agents.Diazotization, reduction to the hydrazine and N-heterocycle formationcan be carried out to afford the isoquinazolin-1-one N-linked to theappropriate heterocycle. For compounds which are C-linked to heterocycleM, the reaction of 5-bromoanthranilic acid with formamide at 150° C.affords the 7-bromoisoquinazolin-1-one. This bromide can be convertedinto an aldehyde or acetyl group which can be then converted into theappropriate C-linked heterocycle.

The compounds of the present invention in which the D-E residue isisoquinolin-1-one can be prepared as described in Scheme 12. Forcompounds which are N-linked to heterocycle M, oxidation of7-nitroisoquinoline to its corresponding N-oxide followed by sequentialtreatment with acetic anhydride and then hydroxide will produce thedesired 7-nitroisoquinolin-1-one. This transformation can be carried outwith other reagents as well. Reduction of the nitro group and subsequentformation of the N-heterocycle will afford the isoquinolin-1-oneN-linked to the appropriate heterocycle. For compounds which areC-linked to heterocycle M, analogous chemistry can be used to preparedesired 7-bromoisoquinolin-1-one, which can then be converted into theappropriate aldehyde or acetyl group for subsequent conversion to theC-linked heterocycle. One method for conversion of the bromide to anacetyl group employs palladium catalysed-coupling with(ethoxyvinyl)tributyltin followed by acid hydrolysis of the intermediatevinyl ether residue.

Compounds wherein D-E is 3-aminobenzisothiazole are exemplified bysynthesis on the pyrazole core as shown in Scheme 13. The4-fluoro-3-cyano-pyrazole intermediate as described previously can beused. Displacement of the fluoro substituent via nucleophilic aromaticsubstitution methodology with a thio nucleophile followed by thestandard Weinreb coupling methodology should afford the desired coupledthiobenzyl intermediate. The nitrile can be converted to the amidine viastandard conditions. Oxidation of the sulfide to the sulfoxide withMCPBA followed by the standard closure adopted by Wright et al for theisothiazolones with trichloroacetic anhydride should afford the desiredamino-isothiazolones.

Compounds in which the M-heterocycle is thiazole can be preparedaccording to the procedures described in Scheme 14. The appropriateQ-D-E bromide can be converted into a beta-keto ester in several ways.One preferred method involves transmetallation with an alkyllithiumreagent followed by quenching with DMF to afford the correspondingaldehyde. Addition of ethyl diazoacetate in the presence of tin (II)chloride affords the beta-keto ester directly. Other methods areavailable for this conversion, one of which involves Reformatskyreaction of the aldehyde followed by oxidation to the beta-keto ester.

A second method for converting the bromide into a beta-keto esterinvolves palladium catalysed coupling with (ethoxyvinyl)tributyltinfollowed by acidic hydrolysis to afford the corresponding acetylderivative. Many methods exist for conversion of the acetyl derivativeto the beta-keto ester, one preferred method involves reacting theacetyl derivative with a dialkyl carbonate in the presence of a basesuch as sodium hydride or lithium diisopropylamide. The beta-keto estercan be converted into the corresponding thiazole derivatives bybromination with NBS followed by cyclization with an appropriatethiourea or thioamide in a solvent such as ethanol or tetrahydrofuran. Aone pot method for this conversion involves treating the beta-keto esterwith hydroxytosyloxyiodobenzene in acetonitrile, which forms anintermediate alpha-tosyloxy-beta-keto ester, followed by addition of athiourea or thioamide to effect cyclization to the correspondingthiazole. Manipulation of the ester group of these thiazoles can thenafford the compounds containing an appropriate Z-A-B group. WhereZ═CONH, standard methods of peptide coupling with an appropriate aminecan be employed, such as reaction of the ester with an aluminum reagentderived from the amine. Where Z═COCH₂, formation of the acid chloride bystandard methods can be followed by addition of an appropriate zincreagent. The R^(1a) group on the thiazole ring can also be manipulatedto provide a variety of different groups. For example, when thiourea isused as the cyclization partner, a 2-aminothiazole is produced. Thisamino group can be readily diazotized and displaced with the appropriatecopper halide to afford 2-halothiazoles. The halogen atom can then bereadily displaced by a variety of carbon, nitrogen, oxygen and sulfurnucleophiles to produce a wide variety of alkyl, aryl, heteroatom, andheterocyclic derivatives of R^(1a).

The tetrazole compounds of this invention where Z is —CONH— can beprepared as exemplified in Scheme 15. An appropiately substituted amine(D-ENH₂) is acylated with ethyl oxalyl chloride. The resulting amide canbe converted to the tetrazole either by the methods described by Duncia(J. Org. Chem. 1991, 2395–2400) or Thomas (Synthesis 1993, 767–768,1993). The amide can be converted to the iminoyl chloride first and thereacted with NaN₃ to form the 5-carboethoxytetrazole (J. Org. Chem.1993, 58, 32–35 and Bioorg. & Med. Chem. Lett. 1996, 6, 1015–1020). The5-carboethoxytetrazole is then coupled with an appropriate amine (BANH₂)by the method described by Weinreb (Tetr. Lett. 1977, 48, 4171–4174).Final deprotection as described before yields the desire product.

The tetrazole compounds of this invention where Z is —CO— can also beprepared via iminoyl chloride (Chem. Ber. 1961, 94, 1116 and J. Org.Chem. 1976, 41, 1073) using an appropriately substituted acyl chlorideas starting material. The ketone-linker can be reduced to compoundswhere Z is alkyl.

The tetrazole compounds of this invention where Z is —SO₂NH—, —S—,—S(O), SO₂— can be prepared as exemplified in Scheme 16. Appropiatelysubstituted thioisocyanate is reacted with sodium azide to give the5-thiotetrazole (J. Org. Chem. 1967, 32, 3580–3592). The thio-compoundcan be alkylated (J. Org. Chem. 1978, 43, 1197–1200) and then oxidizedto the sulfoxide and sulfone. The thio-compound can also be converted tothe sulfonyl chloride and the reacted with an amine to give the desiredsulfonamide. The tetrazole compounds of this invention where Z is —O—can be prepared via the same method described in Scheme 16 by usingappropiately substituted isocyanate as the startimg material.

The tetrazole compounds of this invention where Z is —NH—, —NHCO—,—NHSO₂— can be prepared from 5-aminotetrazole, which can be prepared bySmiles Rearrangement as shown in Scheme 17. The thio-compound preparedas described in Scheme 3 is alkylated with 2-chloroacetamide. Theresulting compound is then refluxed in ethanolic sodium hydroxide togive the corresponding 5-amino-tetrazole (Chem. Pharm. Bull. 1991, 39,3331–3334). The resulting 5-amino-tetrazole can then be alkylated oracylated to form the desired products.

The N-linked imidazole ring M can be synthesized by the synthetic routeshown in Scheme 18. Alkylation of D-E-NH₂ with 2-bromoethylacetatefollowed by reaction with Gold's reagent in the presence of a base, suchas NaOMe or LDA, form imidazole ring M.

Additional imidazole derivatives can be made by the general proceduresas described in Scheme 18a. Here, P is a protective group for aminogroup. E is a substituted group or groups. G is an aromatic ring (six,six-six or five-six ring). R₁ and/or R₂ is H, a substituted alkyl group,or either V or a precusor of (CH₂)_(n)V. V is nitro, amino, thio,hydroxy, sulfone, sulfonic ester, sulfoxide, ester, acid, or halide. nis 0 and 1. U is aldehyde, ester, acid, amide, amino, thiol, hydroxy,sulfonic acid, sulfonic ester, sulfonyl chloride, or methylene halide.Z, A, and B are the same as those described for formula I.

A general procedure to make 2,4,5-trisubstituted or 4,5-disubstitutedimidazole derivatives is described-in Scheme 18b. The starting ester bcan be obtained by acylation of N,O-dimethylhydroxyamine with ethylmalonyl chloride. After metalation with a lithium reagent, compound acan react with b to give compound c., Compound c can also be directlymade from coupling reaction of a with zinc reagent of ethyl malonylchloride. Compound c can be brominated with NBS to form compound d,which can react with excess NH₃ and R₁CO₂H to afford compound e Theester group in e can be transferred to other functionalities, which canbe further reacted to give compound f.

The general procedure to make C-linked imidazole ring M is described inScheme 19. Aldehyde D-E-CHO from Scheme 1 can be converted into cyanocompound by treatment with hydroxyamine and then dehydration with POCl₃.The amidine can be obtained from cyano compound by Pinner reaction,which can be cyclized with alpha-halo ester, ketone or aldehyde to formimidazole ring M.

Pyrazole ring M of the general Formula I such as those described inScheme 1 can be prepared by the condensation of an appropriatelysubstituted hydrazine with a variety of diketo esters. Condensations ofthis type typically afford a mixture of pyrazole regioisomers which canbe effectively separated via silica gel column chromatography (Scheme20). Hydrolysis of the esters followed by coupling with an appropriateamine can afford the desired amide intermediate. Various substituents onthe pyrazole can then be manipulated to afford a variety of benzo,heterocyclic and bicylic compounds.

The above methodology when applied to diketo derivatives also affords amixture of pyrazole regioisomers. These can be further manipulated toafford the compounds of Formula I as shown in Scheme 21.

When ketoimidates are used for condensations with hydrazines thecorresponding pyrazole amino esters regioadducts are obtained (Scheme22). Conversion of these intermediates to the final compounds of formulaI can then be accomplished by the protection of the amino functionalitywith a suitable protecting group commonly known to those in the art orby derivatization (e.g. sulfonamide) then following the generalsynthetic strategy to prepare the compounds of this invention.

The pyrazole ester intermediate can be further manipulated to theketones by the cuprate methodology described by Knochel et al (Scheme23). Alternatively the ester can be reduced to either the alcohol oraldehyde via methods known to those in the art followed by either areductive amination with an appropriate amine to an alkyl amine or byconverting the alcohol to a leaving group which in turn can be displacedwith a number of nucleophiles to provide the intermediates which onfurther manipulations should afford the compounds of this invention.

Thio compounds such as those described in Scheme 24 can be easilyprepared by the conversion of 5-hydroxy pyrazole to its thiol bytreatment with Lawesson's reagent in refluxing toluene.

Compounds of this invention wherein the pyrazole ring M is replaced witha 1,2,3-triazole can be prepared as outlined in Scheme 25.

The compounds of this invention where the ring M is 1,2,4-triazole canbe easily obtained by the methodology of Huisgen et. al. (Liebigs Ann.Chem. 1962, 653, 105) by the cycloaddition of nitriliminium species(derived from the treatment of triethylamine and chloro hydrazone) andan appropriate nitrile dipolarophile as in Scheme 26.

This methodology provides a wide variety of 1,2,4 triazoles with avaried substitution pattern at the 1,3 and 5 positions. Alternativelythe 1,2,4 triazoles can also be prepared by the methodology of Zecchi etal (Synthesis 1986, 9, 772) via an aza Wittig condensation (Scheme 27).

Alternatively the 1,2,4 triazoles can also be prepared via themethodology of Sauer et al (Tetr. Lett. 1968, 325) by the photolysis ofa cyclic carbonate with an appropriate nitile (Scheme 28).

For compounds of this invention the esters can be converted to the amideintermediates via the Weinreb methodology (Tetr. Lett. 1977, 48, 4171),i.e., the condensation of an appropriate amine aluminum complex with theester (Scheme 29).

Isoxazoline ring M of formula I wherein the 4 and 5 positions aresubstituted can be prepared following the 1,3-dipolar cycloadditionmethodology outlined in Scheme 30. An appropriate benzhydroximinoylchloride or heterocyclic oximinoylchloride or oxime when subjected to1,3-dipolar cycloaddition protocol with a suitable 1,2-disubstitutedolefin as a dipolarophile should afford a mixture of regioisomers.Separation of the regioisomers by column chromatography followed by thesequence of reactions as described previously should then afford thecompounds of choice. Optically active isoxazolines can also be obtainedby enzymatic resolution on the regioisomeric esters or by the use of anappropriate chiral auxilliary on the dipolarophile as described byOlsson et al (J. Org. Chem. 1988, 53, 2468).

In the case of compounds with general formula I wherein Z is an amidethe cycloaddition process described in Scheme 30 utilizes anappropriately substituted crotonate ester. The crotonate esters can beobtained from commercial sources or can be obtained fromethyl-4-bromocrotonate by nucleophilic displacement reactions shown inScheme 31.

Trisubstituted olefins as dipolarophiles can be obtained fromethylpropiolate by the cuprate chemistry (Scheme 32) according to themethod described by Deslongchamps et al (Synlett 1994, 660).

Compounds of this invention with 1,3,4-triazole ring M can be easilyobtained via the methodology of Moderhack et al (J. Prakt. Chem. 1996,338, 169) as in Scheme 33.

This reaction involves the condensation of a carbazide with anappropriately substituted commercially available thio-isocyanate to thecyclic thiourea derivative as described previously. Alkylation ornucleophilic displacement reactions on the thiono intermediate thenaffords a thio alkyl or aryl intermediate which can be hydrolysed,oxidized and decarboxylated to the 5-H-2-thio-triazole intermediatewhich can be effectively converted to the compounds of this invention.Alternatively the thiono urea intermediate can be oxidized directly tothe 2-H-triazole which can then be converted to the ester and thensubjected to a variety of reactions shown above to obtain the compoundsof this invention. The esters can also be converted to the amine via theHoffmann rearrangement and this methodology provides a variety ofanalogs similar to those shown previously. The cyclic thiono ureaintermediate can also be oxidized to the sulfonyl chloride by methodsshown previously. This in turn can provide the sulfonamides shown inScheme 34.

Scheme 35 describes the general synthesis for pyrazoles which have thioand oxidized sulfur derivatives. An appropriately substituted amine isalkylated with ethyl bromoacetate and hydrolyzed to the glycinederivative. Preparation of the N-nitroso compound was easily achievedwith sodium nitrite (J. Chem. Soc. 1935, 899). Cyclization to thesyndone using acetic anhydride (J. Chem. Soc. 1935, 899) was followingby the introduction of the sulfide unit using a sulfoxide as solvent andacetyl chloride as a activating reagent (Tetr. 1974, 30, 409).Photolytic cleavage of the sydnone in the presence of an acetyleniccompound the 1,3,5 trisubstituted pyrazole as the major regioisomer(Chem. Ber. 1979, 112, 1206). These can be carried on, as describedbefore, to the final compounds containing the sulfide, sulfoxide orsulfone functionality.

Scheme 36 shows one possible synthesis of isoxazoles. Substitutedbenzaldehydes are reacted with hydroxylamine then chlorinated to givethe hydroximinoyl chloride according to the procedure of (J. Org. Chem.1980, 45, 3916). Preparation of the nitrile oxide in situ withtriethylamine and cycloaddition with a substituted alkyne gives amixture of regioisomeric isoxazoles as shown by H. Kawakami (Chem. Lett.1987, 1, 85). Preparation of the disubstituted alkyne is achieved bynucleophilic attack of the alkynyl anion on an electrophile as shown byJungheim et al (J. Org. Chem. 1987, 57, 4007).

Alternatively, one could make the hydroxyiminoyl chloride of the R^(1a)piece and react it with an appropriately substituted alkyne to giveanother set of regioisomeric isoxazoles which can be separatedchromatographically.

An alternate procedure which produces only one regioisomer is describedin Scheme 37. The methylated form of V can be deprotonated andsilylated. Chlorination with carbon tetrachloride or fluorination withdifluorodibromo-methane under triethylborane catalysis give the geminaldihalo compound as shown by Sugimoto (Chem. Lett. 1991, 1319).Cuprate-mediated conjugate addition-elimination give the desired alkeneas in Harding (J. Org. Chem. 1978, 43, 3874).

Alternatively, one can acylate with an acid chloride to form a ketone asin Andrews (Tetr. Lett. 1991, 7731) followed by diazomethane to form theenol ether. Each of these compounds can be reacted with a hydroximinoylchloride in the presence of triethylamine to give one regioisomericisoxazole as shown by Stevens (Tetr. Lett. 1984, 4587).

When core substitutent R^(1a) is CH₂—R^(1′), the synthesis is shown inScheme 38. After being treated with LDA, the ketone starting materialreacts with PhSSO₂Ph to give the phenylthiolated compound which reactswith hydrazine in acetic acid to form pyrazole derivative. The pyrazoleester reacts with an amine or aniline (previously treated with AlMe₃) toprovide amide. Oxidation of the sulfide with mCPBA gives thecorresponding sulfone. Deprotonation of the sulfone with base, followedby trapping with an electrophile(E-X) and treatment with SmI₂ providedthe desired compound after deprotection.

Scheme 39 shows other methods of synthesis for R^(1a)=CH₂R^(1′) orCOR^(1′). Protection of the hydroxyl group of hydroxyacetone with abenzyl halide and treatment with a base and CO(CO₂Et)₂ gives thetricarbonyl compound. Refluxing with NH₂OMe.HCl in pyridine and ethanolin the presence of molecular sieve 3 Å gives the oxime. Cyclization ofoxime with D-E-NHNH₂ provided pyrazole, which can be converted into thecorresponding amide by reacting with an amine or aniline (previouslyactivated with AlMe₃). Debenzylation by catalytic hydrogenation providesthe alcohol. The alcohol is converted into the tosylate with TsCl,followed by replacement with a nucleophile to provide the desiredcompound. The alcohol can also be oxidized to the corresponding aldehydeor acid, or further converted to ester or amide.

Scheme 40 shows the synthesis of pyrazole ring with a chloride group.Chlorination of pyrazole starting material obtained previously in Scheme2a with NCS formed chloropyrazole. The chloropyrazole can be reactedwith an aniline in the presence of AlMe₃ followed by amination asdescribed in Scheme 2a to give the desired product.

Scheme 41 describes the synthesis of compounds wherein M is a benzenering and V is a nitro, protected sulfonamide or ester group andprecursor of group Z of Formula I. The V group is placed on anappropriately substituted phenol either via nitration as shown byPoirier et al. (Tetrahedron 1989, 45(5), 1415), sulfonylation as shownby Kuznetsov (Akad. Nauk SSSR Ser. Khim 1990, 8, 1888) or carboxylationby Sartori et al. (Synthesis 1988, 10, 763). Bromination withtriphenylphosphine and bromine (J. Am. Chem. Soc. 1964, 86, 964) givesthe desired bromide. Suzuki coupling with the appropriate boronic acidprovides the desired substituted pyridine.

Schemes 42–45 describe the synthesis of compounds wherein M is pyridine.Each scheme represents a different substitution pattern for the pyridinering. In Scheme 42, a suitably protected aldehyde is subjected tobase-catalyzed condensation with an activated ester to give afterdeprotection the desired aldehyde. Refluxing with ammonium chloride asshown by Dornow and Ische (Chem. Ber. 1956, 89, 876) provides thepyridinol which is brominated with POBr₃ (Tjeenk et al. Rec. Trav. Chim.1948, 67, 380) to give the desired 2-bromopyridine. Suzuki coupling withthe appropriate boronic acid provides the desired substituted pyridine.

Treatment of an appropriately substituted 5-ethoxyoxazole with an alkeneas shown by Kondrat'eva et al. (Dokl. Akad. Nauk SSSR 1965, 164, 816)provides a pyridine with the V substituent at the para position.Bromination at the 3-position as shown by van der Does and Hertog (Rec.Trav. Khim. Pays-Bas 1965, 84, 951) followed by palladium-catalyzedboronic acid coupling provides the desired substituted pyridine.

Scheme 44 describes a synthesis of a third substitution pattern on apyridine ring. The appropriate tricarbonyl compound which can beprepared by methods described in Scheme 42 is treated with ammoniumchloride to form the pyridinol which is subsequently brominated.Palladium-catalyzed coupling provides the desired substituted pyridine.

Scheme 45 takes a suitably substituted dicarbonyl compound and bychemistry illustrated in Schemes 42 and 44, reacts it with ammoniumchloride. Bromination gives the 3-bromopyridine which uponpalladium-catalyzed coupling provides the desired substituted pyridine.

Schemes 46–48 describe the synthesis of compounds wherein M ispyridazine. Each scheme represents a different substitution pattern forthe pyridine ring. In Scheme 46 an activated ester is reacted with anappropriately substituted α-keto aldehyde and hydrazine as shown bySchmidt and Druey (Helv. Chim. Acta 1954, 37, 134 and 1467). Conversionof the pyridazinone to the bromide using POBr₃ and palladium-catalyzedcoupling provides the desired substituted pyridazine.

In Scheme 47, glyoxal can react under basic conditions with an activatedketone and subsequently brominated/dehydrobrominated to give the desiredketoaldehyde. Alternatively, a protected ketone can react with anactivated aldehyde, undergo bromination/dehydro-bromination, bedeprotected and oxidized to give the regioisomeric ketoaldehyde.Cyclization as shown by Sprio and Madonia (Ann. Chim. 1958, 48, 1316)with hydrazine followed by palladium-catalyzed coupling provides thedesired substituted pyridazine.

By analogy to Scheme 47, in Scheme 48, a aldehyde can be reacted with anactivated ketone, brominated, dehydro-brominated and deprotected to givethe desired diketone. Alternatively, a regioisomeric ketone can beplaced through the same reaction sequence to produce an isomeric ketoaldehyde. Reaction with hydrazine followed by palladium-catalyzedcoupling provides the desired substituted pyridazine.

Schemes 49 and 50 describe the synthesis of compounds wherein M ispyrimidine. Each scheme represents a different substitution pattern forthe pyrimidine ring. In Scheme 49, a condensation with an appropriatelysubstituted acid chloride and an activated ester followed by conjugatereduction by tin hydride (Moriya et al. J. Org. Chem. 1986, 51, 4708)gives the desired 1,4 dicarbonyl compound. Cyclization with formamidineor a substituted amidine followed by bromination gives the desiredregioisomeric pyrimidine. Palladium-catalyzed coupling provides thedesired substituted pyrimidine.

Using similar chemistry, Scheme 50 shows how an amidine can be condensedwith a 1,3-dicarbonyl compound and subsequently brominated in the5-position (J. Het. Chem. 1973, 10, 153) to give a specificregioisomeric bromopyrimidine. Palladium-catalyzed coupling provides thedesired substituted pyrimidine.

Using the same ketoaldehyde from Scheme 50, cyclization with anappropriately substituted 1,2-diamine (Chimia 1967, 21, 510) followed byaromatization (Helv. Chim. Acta 1967, 50, 1754) provides a regioisomericmixture of pyrazines as illustrated in Scheme 51. Bromination of thehydrobromide salt (U.S. Pat. No. 2,403,710) yields the intermediate forthe palladium-catalyzed coupling step which occurs as shown above.

Schemes 52 and 53 describe the synthesis of compounds wherein M is a1,2,3-triazine. In Scheme 52, a vinyl bromide is palladium coupled to amolecule containing the substituent R^(1b). Allylic bromination followedby azide displacement provide the cyclization precursor.Triphenylphosphine-mediated cyclization (J. Org. Chem. 1990, 55, 4724)give the 1-aminopyrazole which is subsequently brominated withN-bromosuccimide. Lead tetraacetate mediated rearrangement as shown byNeunhoeffer et al. (Ann. 1985, 1732) provides the desired regioisomeric1,2,3-triazine. Palladium-catalyzed coupling provides the substitutedtriazine.

In Scheme 53, an alkene is allylically brominated and the bromide isdisplaced to give a regioisomer of the azide in Scheme 52. Following thesame reaction sequence as shown above, cyclization provides the1-aminopyrazole. Bromination followed by lead tetraacetate mediatedrearrangement give the 1,2,3-triazine. Palladium-catalyzed couplingprovides the other desired triazine.

Schemes 54 and 55 describe the synthesis of compounds wherein M is a1,2,4-triazine. In Scheme 54, a nitrile is converted using hydrazine togive the amidrazone which is condensed with a α-ketoester to give thetriazinone as shown by Paudler and Lee (J. Org. Chem. 1971, 36, 3921).Bromination as shown by Rykowski and van der Plas (J. Org. Chem. 1987,52, 71) followed by palladium-catalyzed coupling provides the desired1,2,4-triazine.

In Scheme 55, to achieve the opposite regioisomer the reaction schemeshown above is modify by the substituting a protect α-ketoester. Thisallows the most nucleophilic nitrogen to attack the ester functionalitysetting up the opposite regiochemistry. Deprotection and thermalcyclization gives the triazinone which is brominated as shown above.Palladium-catalyzed coupling provides the other desired 1,2,4-triazine.

Scheme 56 describes the synthesis of compounds wherein M is a1,2,3,4-tetrazine. Lithiation of a vinyl bromide, transmetallation withtin, palladium catalyzed carbonylation and hydrazone formation providesa diene for a subsequent Diels-Alder reaction as shown by Carboni andLindsey (J. Am. Chem. Soc. 1959, 81, 4342). Reaction with dibenzylazodicarboxylate followed by catalytic hydrogenation to debenzylate anddecarboxylate should give after bromination the desired1,2,3,4-tetrazine. Palladium-catalyzed coupling provides the desiredsubstitution.

Compounds of this invention where B is either a carbocyclic orheterocyclic residue as defined in Formula I are coupled to A as showngenerically and by specific example in Scheme 57, either or both of Aand B may be substituted with 0–2 R⁴. W is defined as a suitableprotected nitrogen, such as NO₂ or NHBOC; a protected sulfur, such asS-tBu or SMOM; or a methyl ester. Halogen-metal exchange of the brominein bromo-B with n-butyl lithium, quenching with triisopropyl borate andacidic hydrolysis should give the required boronic acid, B′—B(OH)₂. TheW-A-Br subunit may be already linked to ring M before the Susukicoupling reaction. Deprotection can provide the complete subunit.

Scheme 58 describes a typical example of how the A-B subunit can beprepared for attachment to ring M. 4-Bromoaniline can be protected asBoc-derivative and the coupled to 2-(t-butylamino)sulfonylphenylboronicacid under Suzuki conditions. 2-(t-Butylamino)sulfonylphenylboronic acidcan be prepared by the method described by Rivero (Bioorg. Med. Chem.Lett. 1994, 189). Deprotection with TFA can provide the aminobiphenylcompound. The aminobiphenyl can then be coupled to the core ringstructures as described below.

For N-substituted heterocycles, Scheme 59 shows how the boronic acid canbe formed by a standard literature procedure (Ishiyama, T.; Murata, M.;and Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510). Copper-promoted C—Nbond coupling of the boronic acid and heterocycle can be performed asdescribed (Lam, P. Y. S.; et. al., Tet. Lett. 1998, 39, 2941–2944). Itis preferrable to use boroxine or unhindered borate as the boron source.The acid obtained can be condensed with H-A-B′ and after deprotectionyields the desired product.

A synthetic route for making aminobenzisoxazole derivatives with animidazole core is shown in Scheme 60. Palladium(0)-catalyzedcross-coupling reaction of an alkoxydiboron (pinacol diborate) with ahaloarene (see, Ishiyama et al, J. Org. Chem. 1995, 60, 7508–7510)should afford an arylborate intermediate, which can be hydrolyzed with4M HCl (10 eq.) in a minimum amount of THF at room temperature to givearylboronic acid. 4-Imidazolecarboxylic acid can be converted to4-trifluoromethylimidazole by reacting with SF₄ (3 eq.) and HF (7.5 eq.)in a shaker tube at 40° C. Copper(II)-catalyzed coupling reaction ofarylboronic acid with 4-trifluoromethylimidazole in the presence ofpyridine (5 eq.) and 4 Å molecular sieves in THF should provide1-aryl-4-trifluoromethylimidazole. Lithiation of the imidazole withn-BuLi, followed by quenching with methylchloroformate, can give1-aryl-4-trifluoromethyl-1H-imidazole-5-methylcarboxylate. Nucleophilicreplacement of fluorobenzene with pre-mixed potassium tert-butoxide andacetone oxime followed by treatment with 20% HCl in ethanol can form1-aminobenzisoxazole-4-trifluoromethyl-1H-imidazole-5-methylcarboxylate.The ester may then be converted to an amide by a Weinreb couplingreaction. Alternatively, after the saponification of the ester inaqueous NaOH in THF, the resulting acid can be converted to thecorresponding acyl chloride upon treatment with SOCl₂ or oxalylchloride, followed by reacting with aniline containing an o-substituentto form an amide. Fluorobenzene can similarly be converted toaminobenzisoxazole derivative by treatment with pre-mixed potassiumtert-butoxide and acetone oxime, followed by reaction with 20% HCl inethanol. The ester can also be saponified in aqueous NaOH in THF to givean acid, which then can be coupled with aniline to give amide via acoupling reagent (ex. PyBrop) under basic conditions.

o-Fluorobenzonitrile derivatives with imidazole core can be converted to1-aminoquinazoline-1H-imidazole derivatives by treatment withformamidine salt in pyridine and ethanol (Scheme 61).

Scheme 62 illustrates the preparation of bicyclic core intermediatesleading to compounds with indazole and indole cores. Compounds of thegeneral type can be obtained by the method outlined in Chem. Ber. (1926)35–359. The pyrazole N-oxide can be reduced by any number of methodsincluding triphenylphosphine in refluxing toluene followed by thehydrolysis of the nitrile substituent to a carboxylic acid with basichydrogen peroxide to give indazole intermediate which may be coupled inthe usual way to give indazole product. Indole intermediate may beobtained via the Fischer Indole Synthesis (Org. Syn, Col. Vol. III 725)from an appropriately substituted phenylhydrazine and acetophenone.Further elaboration using standard synthetic methods including theintroduction of a 3-formyl group by treatment with POCl₃ in DMF, theoptional protection of the indole NH with the Sem group(TMSCH₂CH₂OCH2Cl, NaH, DMF) and oxidation of the aldehyde to acarboxylic acid which is now ready for transformation to indole product.

When B is defined as X—Y, the following description applies. Groups Aand B are available either through commercial sources, known in theliterature or readily synthesized by the adaptation of standardprocedures known to practioners skilled in the art of organic synthesis.The required reactive functional groups appended to analogs of A and Bare also available either through commercial sources, known in theliterature or readily synthesized by the adaptation of standardprocedures known to practioners skilled in the art of organic synthesis.In the tables that follow the chemistry required to effect the couplingof A to B is outlined.

TABLE A Preparation of Amide, Ester, Urea, Sulfonamide and Sulfamidelinkages between A and B. then the reactive to give the substituent offollowing product Rxn. No. if A contains: Y is: A—X—Y: 1 A—NHR² as aClC(O)—Y A—NR²—C(O)—Y substituent 2 a secondary NH ClC(O)—Y A—C(O)—Y aspart of a ring or chain 3 A—OH as a ClC(O)—Y A—O—C(O)—Y substituent 4A—NHR² as a ClC(O)—CR²R^(2a)—Y A—NR²—C(O)—CR²R^(2a)—Y substituent 5 asecondary NH ClC(O)—CR²R^(2a)—Y A—C(O)—CR²R^(2a)—Y as part of a ring orchain 6 A—OH as a ClC(O)—CR²R^(2a)—Y A—O—C(O)—CR²R^(2a)—Y substituent 7A—NHR³ as a ClC(O)NR²—Y A—NR²—C(O)NR²—Y substituent 8 a secondary NHClC(O)NR²—Y A—C(O)NR²—Y as part of a ring or chain 9 A—OH as aClC(O)NR²—Y A—O—C(O)NR²—Y substituent 10 A—NHR² as a ClSO₂—Y A—NR²—SO₂—Ysubstituent 11 a secondary NH ClSO₂—Y A—SO₂—Y as part of a ring or chain12 A—NHR² as a ClSO₂—CR²R^(2a)—Y A—NR²—SO₂—CR²R^(2a)—Y substituent 13 asecondary NH ClSO₂—CR²R^(2a)—Y A—SO₂—CR²R^(2a)—Y as part of a ring orchain 14 A—NHR² as a ClSO₂—NR²—Y A—NR²—SO₂—NR²—Y substituent 15 asecondary NH ClSO₂—NR²—Y A—SO₂—NR²—Y as part of a ring or chain 16A—C(O)Cl HO—Y as a A—C(O)—O—Y substituent 17 A—C(O)Cl NHR²—Y as aA—C(O)—NR²—Y substituent 18 A—C(O)Cl a secondary NH A—C(O)—Y as part ofa ring or chain 19 A—CR²R^(2a)C(O)Cl HO—Y as a A—CR²R^(2a)C(O)—O—Ysubstituent 20 A—CR²R^(2a)C(O)Cl NHR²—Y as a A—CR²R^(2a)C(O)—NR²—Ysubstituent 21 A—CR²R^(2a)C(O)Cl a secondary NH A—CR²R^(2a)C(O)—Y aspart of a ring or chain 22 A—SO₂Cl NHR²—Y as a A—SO₂—NR²—Y substituent23 A—SO₂Cl a secondary NH A—SO₂—Y as part of a ring or chain 24A—CR²R^(2a)SO₂Cl NHR²—Y as a A—CR²R^(2a)SO₂—NR²—Y substituent 25A—CR²R^(2a)SO₂Cl a secondary NH A—CR²R^(2a)SO₂—Y as part of a ring orchain

The chemistry of Table A can be carried out in aprotic solvents such asa chlorocarbon, pyridine, benzene or toluene, at temperatures rangingfrom −20° C. to the reflux point of the solvent and with or without atrialkylamine base.

TABLE B Preparation of ketone linkages between A and B. then the to givethe reactive substituent of following product Rxn. No. if A contains: Yis: A—X—Y: 1 A—C(O)Cl BrMg—Y A—C(O)—Y 2 A—CR²R^(2a)C(O)Cl BrMg—YA—CR²R^(2a) ₂C(O)—Y 3 A—C(O)Cl BrMgCR²R^(2a)—Y A—C(O)CR²R^(2a)—Y 4A—CR²R^(2a)C(O)Cl BrMgCR²R^(2a)—Y A—CR²R^(2a)C(O)CR²R^(2a)—Y

The coupling chemistry of Table B can be carried out by a variety ofmethods. The Grignard reagent required for Y is prepared from a halogenanalog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0° C. tothe reflux point of the solvent. This Grignard reagent can be reacteddirectly under very controlled conditions, that is low temeprature (−20°C. or lower) and with a large excess of acid chloride or with catalyticor stoichiometric copper bromide-dimethyl sulfide complex in dimethylsulfide as a solvent or with a variant thereof. Other methods availableinclude transforming the Grignard reagent to the cadmium reagent andcoupling according to the procedure of Carson and Prout (Org. Syn. Col.Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)₃ according toFiandanese et al. (Tetr. Lett. 1984, 4805), or a coupling mediated bymanganese (II) catalysis (Cahiez and Laboue, Tetr. Lett. 1992, 33(31),4437).

TABLE C Preparation of ether and thioether linkages between A and B thenthe reactive to give the Rxn. substituent of following No. if Acontains: Y is: product A—X—Y: 1 A—OH Br—Y A—O—Y 2 A—CR²R^(2a)—OH Br—YA—CR²R^(2a)O—Y 3 A—OH Br—CR²R^(2a)—Y A—OCR²R^(2a)—Y 4 A—SH Br—Y A—S—Y 5A—CR²R^(2a)—SH Br—Y A—CR²R^(2a)S—Y 6 A—SH Br—CR²R^(2a)—Y A—SCR²R^(2a)—Y

The ether and thioether linkages of Table C can be prepared by reactingthe two components in a polar aprotic solvent such as acetone,dimethylformamide or dimethylsulfoxide in the presence of a base such aspotassium carbonate, sodium hydride or potassium t-butoxide attemperature ranging from ambient temperature to the reflux point of thesolvent used.

TABLE D Preparation of —SO— and —SO2— linkages from thioethers of Table3. and it is oxidized and it is oxidized with with Aluminam-chloroperbenzoic (wet)/Oxone acid (Greenhalgh, (Satoh et al., if theSynlett, (1992) Chem. Lett. (1992) Rxn. starting 235) 381), the productNo. material is: the product is: is: 1 A—S—Y A—S(O)—Y A—SO₂—Y 2A—CR²R^(2a)S—Y A—CR²R^(2a)S(O)—Y A—CR²R^(2a)SO₂—Y 3 A—SCR²R^(2a)—YA—S(O)CR²R^(2a)—Y A—SO₂CR²R^(2a)—Y

The thioethers of Table C serve as a convenient starting material forthe preparation of the sulfoxide and sulfone analogs of Table D. Acombination of wet alumina and oxone can provide a reliable reagent forthe oxidation of the thioether to the sulfoxide while m-chloroperbenzoicacid oxidation will give the sulfone.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration fo the invention and are not intended to be limitingthereof.

EXAMPLES Example 11-(1′-Amino-isoquinol-7′-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazole,mesylate salt

7-Aminoisoquinoline (6.26 g, 43.4 mmol) (J. Chem. Soc. 1951, 2851) isadded to 40 mL of concentrated hydrochloric acid at 0° C. Sodium nitrite(3.0 g, 43.4 mmol) is dissolved in 15 mL water, cooled to 0° C., andadded dropwise to the isoquinoline solution. The reaction is stirred for30 min at 0° C. Stannous chloride dihydrate (29.3 g, 130.2 mmol, 3 eq)is dissolved in 25 mL concentrated hydrochloric acid, the solutioncooled to 0° C., and added dropwise to the isoquinoline solution. Thereaction is placed in the refrigerator overnight. The next day theprecipitate is isolated by filtration, washed with 100 mL ice cold brinefollowed by 100 mL of a 2:1 petroleum ether/ethyl ether solution. Thebrown solid is dried under dynamic vacuum overnight. The tin double saltof the isoquinoline (9.0 g, 26 mmol) is suspended in 100 mL glacialacetic acid and ethyl 2,4-dioxopentanoate oxime (4.0 g, 21.3 mmol) addeddropwise. The reaction was brought to reflux overnight. The next day theacetic acid was evaporated and to the residue was added 100 mL water,cooled to 0° C. and neutralized with solid sodium bicarbonate. Thesolution was extracted with ethyl acetate (6×50 mL), dried over sodiumsulfate, and evaporated to give the title compound as a brownish solid(5.15 g, 86% yield) which was >85% of the desired pyazole regioisomer.The material may be purified by silica gel flash chromatography elutingwith 5% methanol in chloroform: ¹H NMR (CDCl₃) δ 1.24 (t, 3H, J=7.1 Hz,OCH₂CH₃), 2.40 (s, 3H, pyrazole CH₃), 4.24 (q, 2H, J=7.1 Hz, OCH₂CH₃),6.89 (s, 1H, pyrazole H), 7.70 (d, 1H, J=5.9 Hz, H4), 7.75 (dd, 1H,J=8.8 Hz, J=2.2 Hz, H6), 7.89 (d, 1H, J=8.8 Hz, H5), 8.05 (d, 1H, J=2.0Hz, H7), 8.58 (s, 1H, J=5.9 Hz, H3), 9.29 (s, 1H, H1), MS (ES+): 282.1(M+H)⁺ (100%), C₃₀H₂₉N₅O₃S 539.65.

To a solution of 2′-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine(2.19 g, 7.19 mmol) in 100 mL of anhydrous dichloromethane under anatmosphere of nitrogen was added dropwise trimethyl aluminium (10.9 mL,21.6 mmol, 2M in hexane). The solution was stirred for 30 min at ambienttemperature. Ethyl 1-(isoquinolyn-7′-yl)-3-methyl-5-pyrazole carboxylate(2.02 g, 7.19 mmol) in 70 mL of anhydrous dichloromethane was addeddropwise and the reaction warmed to 40° C. and allowed to stir for 15hours. The reaction was quenched with 50 mL 1N hydrochloric acid at 0°C., diluted with 50 mL water and made basic with solid sodium carbonate.The phases are separated and the aqueous extracted with dichloromethane(3×30 mL), dried over sodium sulfate, and evaporated to give the amide(3.50 g, 90% yield) as a brown solid and of sufficient purity for thenext step. The material may be purified by silica gel flashchromatography eluting with 5% methanol in chloroform. MS (ES+): 540.22(M+H)⁺ (100%). The amide was dissolved in 60 mL acetone to which wasadded meta-chloroperbenzoic acid (70%)(1.86 g, 7.55 mmol) and thereaction allowed to stir overnight at ambient temperature. The next daythe solvent was removed under reduced pressure and the residue taken upin 100 mL each of ethyl acetate and saturated sodium bicarbonate. Thephases are separated and the organic dried over sodium sulfate, andevaporated to give the N-oxide as a pale red solid in quantitative yieldand of sufficient purity for the next step. MS (ES+): 556.20 (M+H)⁺(15%); 578.21 (M+Na)⁺ (100%).

The N-oxide was dissolved in 110 mL of anhydrous pyridine and tosylchloride (1.64 g, 8.63 mmol) was added in three equal portions and thereaction allowed to stir at ambient temperature overnight. The pyridinewas removed under reduced pressure and to the residue was added 45 mLethanolamine and the reaction stirred at ambient temperature for 2 days.The reaction was poured onto cracked ice and the solids isolated byfiltration and dried under vacuum to yield 2.33 g (65% yield) of amixture of 1-aminoisoquinoline (major) and 4-aminoisoquinoline (minor)products as a tan solid. MS (ES+) 555.22 (M+H)⁺ (100%), HRMS (FAB+) forC₃₀H₃₀N₆O₃S calc. (M+H)⁺ 555.217836. found 555.21858.

To 20 mL of trifluoroactic acid was added the 1-aminoisoquinolinecompound and the reaction brought to reflux overnight. The next day thesolvent was removed under reduced pressure and the residue made basicwith aqueous sodium carbonate cooled to 0° C., extracted with ethylacetate (3×40 mL), dried over sodium sulfate, and evaporated. The tansolid was purified by silica gel flash column chromatography elutingwith 15% MeOH/CHCl₃ to give 1.60 g (76% yield) of the title compound asa light tan solid. MS (ES+) 499.14 (M+H)⁺ (100%), HRMS (FAB+) forC₂₆H₂₂N₆O₃S calc. (M+H)⁺ 499.155236. found 499.153551.

The product was then treated with one equivalent of methane sulfonicacid in THF. Evaporation of the solvent gave Example 1, MS (ES+) 499.0(M+H)⁺ (100%), mp 195° C.

Example 21-(1′-Amino-isoquinol-7′-yl)-3-methyl-5-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazolemesylate

The title compound was prepared analogously to Example 1. MS (ES+) 498.0(M+H)⁺ (100%), mp 175° C.

Example 31-(4′-Amino-isoquinol-7′-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazole

The title compound was prepared analogously to Example 1. MS (ES+) 499.0(M+H)⁺ (100%), mp 204° C.

Example 41-(Isoquinol-7′-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazole

The title compound was prepared analogously to Example 1. MS (ES+) 484.1(M+H)⁺ (100%).

Example 53-(1′-Amino-isoquinol-7′-yl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]-5-methylisoxazoline

The title compound was prepared analogously to Example 1. MS (ES+) 502.3(M+H)⁺ (100%).

Example 63-(Isoquinol-5′-yl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]-5-methylisoxazoline

The title compound was prepared analogously to Example 1. MS (ES+) 487.3(M+H)⁺ (100%).

Example 73-(Isoquinol-7′-yl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]-5-methylisoxazoline

The title compound was prepared analogously to Example 1. MS (ES+) 487.3(M+H)⁺ (100%).

Example 83-(2′-Aminobenzimidazol-5′-yl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-5-methylisoxazoline

To a solution of methyl 3,4-diaminobenzoate (7.50 g) in methanol (225mL) was added N,N′-dicarbobenzyloxy methyl isothiourea (16.20 g). Thereaction mixture was brought to reflux for 4 h. Heat was removed and themixture was allowed to cool. The stirring was continued at rt forovernight. The precipitate was filtered and washed with ether (40 mL)and air dried to give2-benzyloxycarbonylamino-5-methoxycarbonylbenzimidazole (9.80 g) as apurple solid. ESI mass spectrum z (rel. intensity) 326 (M+H. 100).

A suspension of benzimidazole (1.58 g) in methylene chloride (40 mL) wascooled to −78° C. DIBAL (1.0 M in CH₂Cl₂, 21.87 mL) was added viasyringe. The reaction mixture was stirred at −78° C. for 1.5 h. andslowly warmed up to rt. The reaction was quenched with methanol (2 mL),HCl (5%, 2 mL). The solvent was removed and the residue partitionedbetween ethyl acetate (60 mL) and water (60 mL), washed with water (2×40mL), brine (40 mL); dried over sodium sulfate, to give2-benzyloxycarbonylamino-5-hydroxymethylbenzimidazole (1.2 g). ESI massspectrum z (rel. intensity) 298 (M+H, 100).

To a solution of pyridine (3.83 g) in methylene chloride (30 mL) wasadded CrO₃ (2.42 g). The mixture was stirred at rt for 45 minutesfollowed by addition of a solution of2-benzyloxycarbonylamino-5-hydroxymethylbenzimidazole (1.2 g) inmethylene chloride (20 mL) and DMF (10 mL). The reaction mixture wasstirred at rt for 2.5 h. Two thirds of the solvent was removed and theresidue was partitioned between ethyl acetate and sodium bicarbonate(sat.), washed with KHSO₄ (5% in H₂O), water and brine; dried oversodium sulfate to give aldehyde (0.95 g). ESI mass spectrum z (rel.intensity) 296 (M+H, 100).

To a solution of aldehyde (0.50 g) in ethanol was added a solution ofhydroxyamine hydrochloride (0.15 g) in water (5 mL) and a solution ofsodium acetate (0.28 g) in water (5 mL). The reaction mixture wasstirred at rt overnight. Next day, ethanol was removed and the whiteprecipitate was filtered, washed with water and air dried to give theoxime (0.50 g). ESI mass spectrum z (rel. intensity) 311 (M+H, 100).

To a solution of 2-benzyloxycarbonylamino-5-oximebenzimidazole (0.31 g)in THF (50 mL) was added methyl acrylic acid (0.11 g), to this mixturewas added bleach (5.25%, 2.4 mL) dropwise at 0° C. under stirring. Afteraddition of bleach, the stirring was continued at rt overnight. Most ofthe solvent was removed and the mixture was partitioned between ethylacetate and water. The organic was separated and washed with water,brine; dried over sodium sulfate. The resulting solid was recrystallizedusing methylene chloride/hexane (1:1) to give isoxazoline (0.25 g) as apure compound. ESI mass spectrum z (rel. intensity) 395 (M+H, 100).

To a solution of isoxazoline (100 mg) in DMF (5 mL) was addedtriethylamine (39 mg),(2′-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-yl)amine (115 mg) and BOP(168 mg). The reaction mixture was stirred at 55° C. overnight. Nextday, the mixture was partitioned between ethylacetate (25 mL) and water(25 mL), washed with HCl (5%, 4×10 mL), sodium bicarbonate (5%, 2×10mL), water (2×10 mL) and brine (10 mL); dried over sodium sulfate,filtered and concentrated to leave3-(2-benzyloxycarbonylamino-5-yl)-5-[(2′-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-yl)aminocarbonyl]-5-methylisoxazoline(120 mg). ESI mass spectrum z (rel. intensity) 681 (M+H, 100).

3-(2-Benzyloxycarbonylamino-5-yl)-5-[(2′-tert.butylaminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-5-methylisoxazoline(100 mg) was dissolved in TFA (4 mL). The resulting solution was broughtto reflux for 3 h., cooled to room temperature, stripped off TFA,partitioned between ethylacetate and sodium bicarbonate (5%), washedwith water, dried over sodium sulfate, filtered and concentrated. Prep.TLC gave pure title compound (35 mg). ESI mass spectrum z (rel.intensity) 491 (M+H, 100), mp 162° C.

Example 93-(3′-Aminoindazol-5′-yl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-5-methylisoxazoline

To a solution of 2-fluoro-5-methylbenzonitrile (13.50 g) in CCl₄ (500mL) was added NBS (35.60 g) and benzoylperoxide (2.40 g). The reactionmixture was brought to reflux for 16 h. Heat was removed and allow it tocool. The mixture was filtered through silic gel, filtrate wasconcentrated to give a 5:1 mixture (25 g) of2-fluoro-5-bis-bromomethylbenzonitrile and2-fluoro-5-bromomethylbenzonitrile.

The mixture (25 g) was dissolved in formic acid (85% in water, 200 mL).The resulting solution was refluxed for 4.5 h. After allowing thereaction mixture to cool to room temperature, most of the formic acidwas stripped off, sodium bicarbonate was added to quench the remainingacid, it was partitioned between ethylacetate and sodium bicarbonate(sat.), washed with water and brine, dried over sodium sulfate, filteredand concentrated, flash chromatography (10% EtOAc in hexane) to give3-cyano-4-fluorobenzaldehyde (12 g) as a white crystal. ¹H NMR (CDCL₃) δ10.0 (S, 1H), 8.15–8.24 (m, 2H), 7.42 (t, 1H) ppm; CI mass spectrum z(rel. intensity) 150 (M+H, 100).

To a solution of 3-cyano-4-fluorobenzaldehyde (1.49 g) in benzene wasadded 1,3-propanediol (0.91 g) and toluenesulfonic acid (0.20 g). Themixture was brought to reflux for 3 hr. with a water trap. Aftercooling, it was partitioned between ethylacetate and water, washed withsodium bicarbonate (15% in water), water, brine and water; dried oversodium sulfate, filtered and concentrated to give ketal (1.80 g); ¹H NMR(CDCL₃) δ 7.69–7.80 (m, 2H), 7.20 (t, 1H), 5.48 (s, 1H), 4.24–4.30 (m,2H), 3.95–4.04 (m, 2H), 2.12–2.28 (m, 1H), 1.45–1.52 (m, 1H) ppm; CImass spectrum z (rel. intensity) 207 (M+H, 100).

To a solution of ketal (0.6 g) in n-butanol (10 mL) was added hydrazinemonohydrate (1.45 g). The reaction mixture was brought to reflux for 3hr, cooled to room temperature, quenched with pH 5 buffer solution,partitioned between methylene chloride and water. The organic phase wasseparated and washed with NH₄Cl (sat.), 3×H₂O, dried over sodiumsulfate, filtered and concentrated to give ketal (0.45 g). CI massspectrum z (rel. intensity) 220 (M+H, 100).

To a solution of ketal (0.42 g) in methylene chloride was added TEA (1.6mL) and di-tert-butyl-dicarbonate (2.4 g). The mixture was stirred atroom temperature overnight. The mixture was partitioned betweenmethylene chloride and water, washed with pH 5 buffer solution, waterand brine; dried over sodium sulfate and concentrated to give1-tert-butoxycarbonyl-3-tert-butoxyaminoindazole-5-aldehydedioxane (0.55g). CI mass spectrum z (rel. intensity) 420 (M+H, 100).

To a solution of indazole (0.55 g) in acetone (10 mL) was added toluenesulfonic acid (100 mg). The reaction mixture was stirred at rt for 2 h.Acetone was removed and the residue was partitioned between ethylacetate and water, washed with 2×H₂O, brine and dried over sodiumsulfate. Flash chromatography gave1-tert-butoxycarbonyl-3-tert-butoxycarbonylamino-5-hydrogencarbonylindazole(0.3 g). CI mass spectrum z (rel. intensity) 362 (M+H, 100).

To a solution of indazole (0.30 g) in ethanol (6 mL) was added asolution of hydroxyamine hydrochloride (0.07 g) in water (1 mL) andanother solution of sodium acetate (0.14 g) in water (1 mL). The mixturewas stirred at rt overnight. Ethanol was removed and the resulting solidwas filtered, washed with water and air dried to give aldoxime.

To a solution of aldoxime (0.22 g) in THF was added 2-methyacrylic acid(0.06 g) followed by dropwise addition of bleach (1.4 mL) at 0° C. withvigorous stirring. After the addition, reaction mixture was slowlywarmed to rt and stirred at rt overnight. Partitioned betweenethylacetate and HCl (5%), washed with 3×H₂O, dried over sodium sulfate,filtered and concentrated, flash chromatography to give isoxazoline(0.14 g).

To a solution of isoxazoline (0.14 g) in DMF (6 mL) was added2′-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (0.14 mg), TEA(0.05 g) and BOP reagent (0.2 g). The mixture was stirred at 50° C.overnight; partitioned between ethylacetate and water, washed withbrine, 4× water, dried over sodium sulfate, filtered, concentrated andflash chromatographed to give an isoxazoline (0.06 g). ESI mass spectrumz (rel. intensity) 747 (M+H, 100).

The isoxazoline (0.06 g) was dissolved in TFA (5 mL). The resultingsolution was brought to reflux for 1.5 h. The mixture was stripped offTFA, partitioned between ethylacetate and sodium bicarbonate (5%),washed with 2× water, dried over sodium sulfate, filtered andconcentrated. Prep. TLC afforded example 9 (5 mg). ESI mass spectrum z(rel. intensity) 491 (M+H, 100), mp 157–159° C.

Example 103-(3′-Aminobenzisoxazol-5′-yl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-5-methylisoxazoline

To a solution of 3-cyano-4-fluorobenzaldehyde (2.50 g) in ethanol (40mL) was added a solution of hydroxyamine (1.46 g) in water (10 mL), asolution of sodium acetate (2.75 g) in water (10 mL). The mixture wasstirred at rt, overnight. Ethanol was removed and the white precipitatewas filtered, washed with water and air dried to leave3-cyano-4-fluorobenzaldehydeoxime (2.05 g). CI mass spectrum z (rel.intensity) 165 (M+H, 100).

To a solution of 3-cyano-4-fluorobenzaldoxime (2.50 g) in THF (100 mL)was added 2-methylacrylic acid (1.64 g). The mixture was cooled to 0° C.on an ice bath followed by dropwise addition of NaOCl (5.25% in water)(37 mL) with vigouros stirring. After the addition, the reaction mixturewas slowly warmed up to rt and stirred at rt overnight. The mixture waspartitioned between ethylacetate and HCl (5% in water), washed withbrine, 2×H₂O, dried over sodium sulfate, filtered and concentrated. Theresulting solid was recrystalized to give3-(4-fluoro-3-cyanophenyl-1-yl)-5-methyl-5-hydroxycarbonylisoxazoline(3.30 g) as a pure compound. ¹H NMR (DMSO-d₆) δ 13.6 (br, 1H), 8.20 (dd,1H), 8.10 (td, 1H), 3.84 (d, 1H), 3.41 (d, 1H), 1.57 (s, 3H) ppm; ESImass spectrum z (rel. intensity) 247 (M−H, 100).

To a solution of acetone oxime (2.60 g) in DMF (10 mL) was addedpotassium tert-butoxide (1.0 M in THF, 2.6 mL) via syringe. The mixturewas stirred at rt 10 minutes, a solution of3-(4-fluoro-3-cyanophen-1-yl)-5-methyl-5-hydroxycarbonylisoxazoline (0.5g) in DMF (5 mL) was added. The reaction mixture was stirred at rtovernight. HCl (5% in water) was added to quench the reaction solution,partitioned between ethylacetate and water, washed with 2×H₂O, brine,2×H₂O, dried over sodium sulfate, filtered and concentrated to leaveisoxazoline (0.51 g) as white crystals. ¹H NMR(CDCl₃) δ 9.09 (br, 1H),7.86 (dd, 1H), 7.78 (d, 1H), 7.59 (d, 1H), 3.87 (d, 1H), 3.27 (d, 1H),2.19 (s, 3H), 2.05 (s, 3H), 1.78 (s, 3H) ppm. CI mass spectrum z (rel.intensity) 302 (M+H, 100).

To a solution of isoxazoline (0.51 g) in ethanol (10 mL) was added HCl(20% in water, 3 mL). The mixture was brought to reflux for 1.5 h.Ethanol was removed and the residue was partitioned between ethylacetate and water, washed with 2× water, dried over sodium sulfate,filtered and concentrated to3-(3-aminobenzisoxazol-5-yl)-5-methyl-5-ethoxycarbonylisoxazoline (0.42g) as white solid. ¹H NMR (CDCl₃) δ7.90 (s, 1H), 7.79 (d, 1H), 7.35, (d,1H), 4.25 (q, 2H), 3.95 (d, 1H), 3.49 (s, 2H), 3.25 (d, 1H), 1.73, (s,3H), 1.30 (s, 3H). CI mass spectrum z (rel. intensity) 290 (M+H, 100).

To a solution of isoxazoline (0.42 g) in THF (10 mL) was added NaOH (10%in water) (10 mL). The mixture was stirred at 60° C. for 1.5 h, cooledto rt and HCl (10% in water) was added dropwise untill pH 4–5. Themixture was partitioned between ethylacetate and water, washed with2×H₂O, dried over sodium sulfate, filtered and concentrated to giveisoxazoline acid (0.32 g) as a pure compound. ¹H NMR (DMSO-d₆) δ 13.25(br, 1H), 8.20 (s, 1H), 7.83 (d, 1H), 7.58 (d, 1H), 6.58 (s, 2H), 3.82(d, 1H), 3.00 (d, 1H), 1.60 (s, 3H) ppm. ESI mass spectrum z (rel.intensity) 262 (M+H, 100).

To a solution of isoxazoline acid (52 mg) in DMF (2 mL) was added TEA(26 mg), 2′-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (79 mg)and BOP reagent (115 mg). The reaction mixture was stirred at 50° C.overnight. Partitioned between ethylacetate and water, washed with 2×H₂Obrine and 2×H₂O, dried over sodium sulfate, filtered and flashchromatographed to elute amide (45 mg). ESI mass spectrum z (rel.intensity) 547 (M+H, 100); mp 144° C.

The amide (40 mg) was dissolved in TFA (2 mL). The resulting solutionwas brought to reflux for 1.5 h., stripped off TFA and flashchromatographed to give the title compound (22 mg) as a pure compound.ESI mass spectrum z (rel. intensity) 492 (M+H, 100), mp 164° C.

Example 111-(3′-Aminobenzisoxazol-5′-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

To a solution of 2-fluoro-5-nitrobenzonitrile (2.0 g) in ethylacetate(50 mL) was added stannous chloride dihydrate (27.0 g). The mixture wasbrought to reflux for 1.5 h and allowed to cool. The mixture waspartitioned between ethyl acetate and sodium bicarbonate (sat. inwater). The aqueous phase was extracted with ethyl acetate four times.The organic phase was washed with 4×H₂O, dried over sodium sulfate,filtered and concentrated to leave 4-fluoro-3-cyanoaniline (1.40 g). CImass spectrum z (rel. intensity) 137 (M+H, 100).

4-Fluoro-3-cyanoaniline (1.4 g) was added to 10 mL of concentratedhydrochloric acid at 0° C. Sodium nitrite (0.71 g) was dissolved inwater (3 mL), cooled to 0° C., and added dropwise to the4-fluoro-3-cyanoaniline solution. The reaction was stirred at 0° C. for30 minutes. Stannous chloride dihydrate (6.95 g) was dissolved in HCl(conc., 4 mL). The solution was cooled to 0° C., and added dropwise tothe 4-fluoro-3-cyanoaniline solution. The reaction was placed in therefrigerator overnight. Next day, the precipitate was isolated byfiltration, washed with ice cold brine (30 mL), followed by a 2:1petrolium ether/ethylether (30 mL) solution. The yellow solid was driedunder vacuum overnight to leave 4-fluoro-3-cyanophenylhyrazine tinchloride (2.5 g).

To a suspension of 4-fluoro-3-cyanophenylhyrazine tin chloride (0.9 g)in acetic acid (15 mL) was added the oxime (0.5 g). The reaction wasbrought to reflux overnight. The next day the acetic acid was evaporatedand the residue was partitioned between ethylacetate and sodiumbicarbonate (sat.). The equeous was extracted by ethylacetate (4×20 mL).The organic phase was washed with water, brine, dried over sodiumsulfate, filtered and concentrated. Flash chromatography gave ethyl1-(4-fluoro-3-cyanophenyl)-3-methyl-5-pyrazole carboxylate (0.7 g) aspure compound. CI mass spectrum z (rel. intensity) 274 (M+H, 100).

To a solution of acetone oxime (70 mg) in DMF (6 mL) was added potassiumtert-butoxide (1.0M in THF, 1.1 mL). The reaction was stirred at rt for15 minutes. A solution of ethyl1-(4-fluoro-3-cyanophenyl)-3-methyl-5-pyrazole carboxylate (0.2 g) inDMF (3 mL) was added to the oxime solution. The reaction was stirred atrt overnight. The next day the reaction was partitioned betweenethylacetate and amonium chloride (sat. in water), washed with brine,4×H₂O, dried over sodium sulfate, filtered and concentrated. Flashchromatography gave1-(4-isopropylideneaminooxy-3-cyanophenyl)-3-methyl-5-pyrazolecarboxylate (0.18 g). CI mass z (rel. intensity) 327 (M+H, 100).

To a solution of1-(4-isopropylideneaminooxy-3-cyanophenyl)-3-methyl-5-pyrazolecarboxylate (0.18 g) in ethanol (5 mL) was added HCl (20%, 3 mL). Thereaction was brought to reflux for 2.5 h, ethanol was evaporated and theresidue was partitioned between ethylacetate and water, washed with2×H₂O, dried over sodium sulfate, filtered and concentrated to give1-(3-aminobenzisoxazole-5-yl)-3-methyl-5-pyrazole carboxylate (0.14 g).CI mass spectrum z (rel. intensity) 287 (M+H, 100).

To a solution of ethyl 1-(3-aminobenzisoxazole-5-yl)-3-methyl-5-pyrazolecarboxylate (0.14 g) in THF (5 mL) was added NaOH (10% in water, 5 mL).The reaction was stirred at 60° C. for 2 h, THF was evaporated, HCl (10%in water) was added dropwisely until the pH was between 4–5, partitionedbetween ethylacetate and water, washed with brine, dried over sodiumsulfate, filtered and concentrated to give1-(3-aminobenzisoxazole-5-yl)-3-methyl-5-pyrazole carboxylic acid (0.11g). ESI mass spectrum z (rel. intensity) 259 (M+H, 100).

To a solution of the pyrazole carboxylic acid (55 mg) in DMF (5 mL) wasadded TEA (33 mg), 2′-tert-butylaminosulfonyl-[1,1′]-biphenyl-4ylamine(97 mg) and BOP reagent (141 mg). The reaction was stirred at 50° C.overnight. The next day the reaction was partitioned betweenethylacetate and water, washed with brine, 4×H₂O, dried over sodiumsulfate, filtered, concentrated and flash chromatography to give amide(85 mg). ESI mass spectrum z (rel. intensity) 567 (M+Na, 100).

The amide was dissolved in TFA (3 mL). The resulting solution wasbrought to reflux for 1 h. TFA was evaporated, flash chromatographed togive the title compound (60 mg) as a white solid. ESI mass spectrum z(rel. intensity) 489 (M+H, 100). mp 186° C.

Example 12–143-(1-Amino-isoquinol-7-yl)-4-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-1,2,3-triazole(Example 12),3-(4-amino-isoquinol-7-yl)-4-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-1,2,3-triazole(Example 13), and3-(isoquinol-7-yl)-4-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-1,2,3-triazole(Example 14)

To a solution of 7-aminoisoquinoline (7.0 g) in TFA (35 mL) at 0° C. wasadded sodium nitrite (4.02 g) portionwise over a period of 30 minutes.The reaction was stirred at 0° C. to room temperature for 1.5 h. Water(3.5 mL) was added followed by portionwise addition of sodium azide(3.48 g) at 0° C. over a period of 30 minutes. After the addition, thereaction was slowly warmed up to room temperature and stirred for 1 h.Two third of TFA was evaporated and the residue was cooled to 0° C.Sodium bicarbonate (sat. in water) was added dropwisely to the residueuntil the pH was abouty 8–9. After extraction with methylene chloride(4×60 mL), the organic phase was combined, washed with water, brine,dried over sodium sulfate, filtered and concentrated to leave7-azidoisoquinoline (7.5 g) as a dark brown solid. CI mass spectrum z(rel. intensity) 171 (M+H, 100).

7-Azidoisoquinoline (7.20 g) was suspended in toluene (80 mL).Propargyladehyde di-ethyl acetal (6.50 g) was added to the7-azidoisoquinoline suspension. The reaction was stirred at roomtemperature overnight. The next day the solvent was evaporated and theresidue was put on flash chromatography to give a mixture (10.25 g) ofregioisomeric triazole aldehyde di-ethyl acetal in a 3:2 ratio by NMR.The mixture was further purified by recrystalization to give1,2,3-triazole (6.50 g) as a pale yellow solid. CI mass spectrum z (rel.intensity) 299 (M+H, 100).

The acetal (1.5 g) was dissolved in TFA (50% in water, 15 mL). Theresulting solution was stirred at room temperature overnight. The nextday the solvent was evaporated and the residue was partitioned betweenethyl acetate and sodium bicarbonate (sat. in water), washed with water,brine, dried over sodium sulfate, filtered and concentrated to givealdehyde (1.0 g) as a white solid. CI mass spectrum z (rel. intensity)225 (M+H, 100).

To a solution of aldehyde (1.0 g) in methanol (25 mL) was added sodiumcyanide (0.44 g), manganese (IV) oxide (6.30 g) and acetic acid (0.27g). The reaction was stirred at room temperature overnight. The next daythe reaction was filtered through celite, the pad was washed with asolution of methanol in methylene chloride (50%). The filtrate wasconcentrated and partitioned between ethylacetate and sodium bicarbonate(sat. in water), washed with water, dried over sodium sulfate, filteredand concentrated to give the carboxylate (0.75 g) as a pure compound. CImass spectrum z (rel. intensity) 255 (M+H, 100).

To a solution of 2′-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine(132 mg) in methylene chloride (8 mL) was added AlMe₃ (2.0 M in hexane,0.6 mL). The resulting solution was stirred at room temperature for 20minutes. A solution of carboxylate (100 mg) in methylene chloride (5 mL)was added. The reaction was stirred at room temperature overnight. Thenext day the solvent was removed and HCl (10% in water, 5 mL) was added.The residue then was basified by the addition of sodium carbonate,partitioned between ethyl acetate and water, washed with sodiumbicarbonate (sat. in water), water, dried over sodium sulfate, filteredand concentrated. Flash chromatography purification gave amide (110 mg)as a pure compound. ESI mass spectrum z (rel. intensity) 549 (M+Na,100).

The amide (20 mg) was dissolved in TFA (2 mL). The resulting solutionwas stirred at 80° C. for 1 h. TFA was evaporated and the residue waspurified on a flash chromatograpy to give3-(isoquinol-7-yl)-4-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-1,2,3-triazole(Example 14) as a pure compound. ESI mass spectrum z (rel. intensity)471 (M+H, 100), mp 230° C.

To a suspension of triazole (80 mg) in methylene chloride (8 mL) wasadded MCPBA (50 mg). The reaction was stirred at reflux for 1 h. Themixture became a clear solution and was cooled to room temperature. Thesolvent was removed and the residue partitioned between ethylacetate andsodium bicarbonate (sat. in water), washed with water, dried over sodiumsulfate, filtered and concentrated to give the desiredisoquinoline-N-oxide (65 mg). To a solution of isoquinolne-N-oxide (65mg) in pyridine (5 mL) was added TsCl (60 mg). The resulting solutionwas stirred at room temperature overnight. The next day the solvent wasstripped off to dryness, ethanol amine (3 mL) was added. The reactionwas stirred at room temperature overnight. The next day, the reactionmixture was partitioned between ethylacetate and water, the equeousphase was extracted with ethyl acetate (3×15 mL). The extracts werecombined, concentrated and flash chromatographed to give thetert-butylaminosulfonyl compound (50 mg). The tert-butylaminosulfonylcompound (50 mg) was refluxed in TFA (4 mL) for 1 h and the TFA strippedoff. The residue was partitioned between ethylacetate and sodiumbicarbonate (sat. in water), washed with water, dried over sodiumsulfate, filtered and concentrated, prep. TLC to give Example 12:3-(1-amino-isoquinol-7-yl)-4-[(2′-aminosulfonyl-[1,1′]-biphenyl-4-yl)aminocarbonyl]-1,2,3-triazole)(20 mg). ESI mass spectrum z (rel. intensity) 486 (M+H, 100), mp 250°C., and Example 13:3-(4-amino-isoquinol-7-yl)-4-[(2′-aminosulfonyl-[1,1′]-biphenyl-4-yl)aminocarbonyl]-1,2,3-triazole(6 mg). ESI mass spectrum z (rel. intensity) 486 (M+H, 100), mp 245° C.

Example 151-(Quinol-2-ylmethyl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 484 (M+H, 100), mp 169° C.

Example 161-(Quinol-2-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 484 (M+H, 100), mp 181° C.

Example 171-(3′-Aminoindazol-5′-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 488 (M+H, 100), mp 203° C.

Example 181-(3-Aminoindazole-5-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 488 (M+H, 100), mp 197° C.

Example 191-(3′-Aminobenzisoxazol-5′-yl)-3-methyl-5-[(2′-aminosulfonyl-(phenyl)pyridy-2-ylaminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 490 (M+H, 100), mp 188° C.

Example 201-(3′-Aminobenzisoxazol-5′-yl)-3-methyl-5-[isoquinol-7-yl)aminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 385 (M+H, 100), mp 210° C.

Example 211-(1′-Aminoisoquinol-7′-yl)-3-ethyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 513 (M+H, 100), mp 201° C.

Example 221-(1′-Aminoisoquinol-7′-yl)-3-isopropyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 527 (M+H, 100), mp 165° C.

Example 231-(2′,4′-Diaminoquinazol-6′-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 515 (M+H, 100), mp 215° C.

Example 241-(4′-Aminoquinazol-6′-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared analogously to Example 12. ESI massspectrum z (rel. intensity) 500 (M+H, 100), mp 205° C.

Example 251-(1′-Aminoisoquinol-7′-yl)-3-methyl-5-[4-(N-pyrrolidinylcarbonyl)phenylaminocarbonyl]pyrazole,trifluoroacetic acid salt

Standard trimethylaluminum (Weinreb protocol) coupling of4-carboxamidopyrrolidinophenyl-aniline withethyl-N1-pyrazole(isoquinol-7-yl)-3-methyl-5-carboxylate, acidic workupand purification via silica gel column chromatography afforded thedesired coupled product in 50% yield. ¹H NMR (CDCl₃) δ: 9.20 (s, 1H),8.89 (bs, 1H), 8.72 (d, 1H), 8.04 (s, 1H), 7.84 (d, 1H), 7.75 (dd, 1H),7.66 (d, 1H), 7.45 (d, 2H), 7.37 (d, 2H), 6.80 (s, 1H), 3.60 (t, 2H),3.39 (t, 2H), 2.40 (s, 1H), 1.84 (m-4H) ppm; ESI mass spectrum m/z (relintensity) 426 (M+H, 100).

The isoquinoline product was then converted to the desired productfollowing oxidation (MCPBA) and rearrangement (pTsCl/pyridine;ethanolamine) described previously. ¹H NMR (DMSO d₆) δ: 8.70 (s, 1H),7.98 (bs, 2H), 7.75 (dd, 4H), 7.46 (d, 2H), 7.27 (d, 1H), 7.09 (s, 1H),3.30 (b, 4H), 2.34 (s, 3H), 7.78 (b, 4H) ppm; ESI mass spectrum m/z (relintensity) 441 (M+H, 100).

Example 261-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazolePreparation of1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-pyrazolecarboxylic acid

Method A:

To a suspension of 4-fluoro-3-cyanophenylhydrazine tin chloride (20 g,53.6 mmol) in ethanol (150 mL) was added1,1,1-trifluoro-2,4-pentanedione (8.18 g, 53.6 mmol). The reaction wasbrought to reflux overnight. The next day the ethanol was evaporated andthe residue partitioned between ethyl acetate and HCl (1 N). The aqueousphase was extracted with ethyl acetate (4×20 mL). The organic phase iswashed with water, brine, dried over sodium sulfate, filtered andconcentrated. Flash chromatography gave1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-methylpyrazole (8 g, 56%yield) as pure compound: MS (CI): 270 (M+H)⁺ (100%).

To a solution of1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-methylpyrazole (4.0 g,14.9 mmol) in CCl₄ (75 mL) was added NBS (5.3 g, 29.7 mmol) andbenzylperoxide (0.2 g, 1.49 mmol). The reaction was brought to refluxovernight. The next day the CCl₄ was evaporated and the residue waspartitioned between ethyl acetate and sodium bicarbonate (sat.). Theorganic phase was washed with water, brine, dried over sodium sulfate,filtered and concentrated. Flash chromatography gave1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-bromomethylpyrazole (2.6g, 50% yield) as pure compound: MS (CI): 348 (M+H)⁺ (100%).

To a solution of1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-bromomethylpyrazole (0.6g, 1.72 mmol) in DMSO (10 mL) was added copper (I) oxide (0.52 g, 3.62mmol) and water (3 mL). The reaction was stirred at 60° C. overnight.The next day the reaction mixture was filtered through celite. Thefiltrate was partitioned between ethyl acetate and water. The organicwas washed three times with water, brine, dried over sodium sulfate,filtered and concentrated to leave1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxymethyl pyrazole(0.45 g, 92% yield) as pure compound: MS (CI): 286 (M+H)⁺ (100%).

To a solution of1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxymethylpyrazole(0.45 g, 1.58 mmol) in acetonitrile (10 mL) was added catalytic amountof ruthenium chloride at 0° C. followed by addition of a solution sodiumperiodate (0.71 g, 3.32 mmol) in water. The reaction was stirred at 0°C. to room temperature overnight. The next day the acetonitrile wasevaporated and the residue was partitioned between ethyl acetate andwater, washed with brine, dried over sodium sulfate, filtered andconcentrated to give1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxycarbonylpyrazole(0.27 g, 57% yield) as pure compound: MS (ES−): 298 (M−H)⁻ (40%).

Method B:

To a suspension of 4-fluoro-3-cyanophenylhyrazine tin chloride (17 g, 50mmol) in acetic acid (200 mL) was added4,4,4-trifluoro-1-(2-furyl)-2,4-butanedione (10.3 g, 50 mmol). Thereaction was brought to reflux overnight. The next day the acetic acidwas evaporated and the residue was partitioned between ethyl acetate andwater, washed with HCl (1N), water and brine, dried over sodium sulfate,filtered and concentrated, flash chromatography to give1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-(2-furyl) pyrazole (7.0g, 44% yield) as pure compound. MS (CI): 322 (M+H)⁺ (100%).

To a solution of1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-(2-furyl)pyrazole (4.0 g,12.5 mmol) in acetonitrile (30 mL) was added carbon tetrachloride (30mL), ruthenium chloride (0.4 g) and a solution of sodium periodate (11.9g, 56.1 mmol) in water (45 mL). The reaction is stirred at roomtemperature overnight. The next day the reaction mixture was filteredthrough celite. The filtrate was concentrated and partitioned betweenethyl acetate and HCl (1N). The organic phase was washed with water,dried over sodium sulfate, filtered and concentrated to give1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxycarbonyl pyrazole(2.4 g, 64% yield) as pure compound. MS (ES−): 298 (M−H)⁻ (40%).

Preparation of1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

To a solution of1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxycarbonylpyrazole(0.2 g, 0.67 mmol) in methylene chloride (10 mL) was added oxalylchloride (0.84 g, 6.7 mmol) and one drop of DMF. The resulting solutionwas stirred at room temperature overnight. The next day the solvent isevaporated and the residue is redissolved in methylene chloride and tothe solution was added(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)amine hydrochloride (0.2g, 0.67 mmol) and DMAP (0.25 g, 2.01 mmol). The reaction was stirred atroom temperature overnight. The next day, methylene chloride wasevaporated and the residue was partitioned between ethyl acetate and HCl(1N), washed with HCl (1N), sodium bicarbonate (sat.), brine and water,dried over sodium sulfate, filtered and concentrated to leave1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (0.32 g, 87% yield) as pure compound. MS (ESI): 547 (M+H)(100%).

Preparation of1-(3′-aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

To a solution of acetone oxime (86 mg, 1.18 mmol) in DMF (6 mL) wasadded sodium t-butoxide (1 M in THF, 1.18 mL). The mixture was stirredat room temperature for half hour followed by addition of a solution of1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole(0.22 g, 0.39 mmol) in DMF (4 mL). The reaction was stirred at roomtemperature for 5 hours. The reaction mixture was then partitionedbetween ethyl acetate and HCl (5%), washed with HCl (5%), four timeswith water, brine, dried over sodium sulfate, filtered and concentrated.Flash chromatography (30% ethyl acetate/hexane) gave1-(4-isopropylideneaminooxy-3-cyanophenyl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole(0.19 g, 81% yield) as pure compound: MS (ESI): 600 (M+H) (100%).

1-(4-Isopropylideneaminooxy-3-cyanophenyl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole(0.19 g, 0.32 mmol) was dissolved in ethanol (4 mL) and to the solutionwas added HCl (20%, 4 mL). The reaction mixture was stirred at 80° C.for three hours. The reaction mixture was cooled to room temperature.The white precipitate was filtered and recrystalized in methanol to givethe title compound (0.14 g, 80% yield): MS (ESI): 501 (M+H) (100%).

Example 271-(1′-Aminopthalazin-7′-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazolePreparation of 3-nitro-6-styrylbenzamide

A mixture of 2-cyano-4-nitrotoluene (10 g, 6.17 mmol), benzaldehyde(6.51 g, 6.17 mmol) and potassium carbonate (20 g) in MeOH (200 mL) washeated at reflux for 10 min. The mixture was cooled to ambienttemperature over 30 min, whereupon precipitation of the product wascomplete. The product was isolated by filtration and washed successivelywith 1N HCl, water and MeOH then air dried. There was obtained 13.0 g ofthe benzamide (mp 269.8° C.) as evident from the lack of a nitrileadsorption in the IR and the appearance of peaks at 3357.1, 3193.6(—NH2) and 1648.7 cm⁻¹ (H2NC(═O)—); LRMS (M−NO)⁺ m/z=238.

Preparation of 3-amino-6-styrylbenzamide

The nitro compound prepared above (13 g, 48.41 mmol) and SnCl₂.H₂O (54.7g, 240 mmol) were combined in EtOH and heated at reflux for 1.5 h. TheEtOH was removed by distillation in vacuo then 30% NaOH added.Extraction of this suspension with EtOAc followed by washing the organicextract with brine, drying (MgSO₄) and evaporation gave the productaniline (13.39 g); LRMS (M+H)⁺ m/z=239.

Preparation of 3-hydrazino-6-styrylbenzamide

The aniline (13 g, 54.6 mmol) from above was dissolved in conc. HCl (90mL) and cooled to 0° C. A solution of NaNO₂ (3.94 g) in water (45 mL)was added dropwise over 10 min and the diazotization mixture left tostir at 0–50C for 1 h. After this time SnCl₂.H2O (39 g) in water (170mL) was added dropwise to the cold mixture over 30 min then allowed tothaw to ambient temperature over 3 h. The solid product was isolated byfiltration, then the filter cake was washed with water several times andair-dried to give the hydrazine contaminated with Sn (II) salts (10.9g).

Preparation of ethyl3-methyl-1-(3-amido-4-styrylphenyl)-1H-pyrazole-5-carboxylate

The phenylhydrazine prepared above (3.2 g) and ethyl2-N-(methoxy)imino-4-oxopentanoate (2.46 g, 13.18 mmol) in AcCN (30 mL)and AcOH (5 mL) were heated at reflux for 4 h. The reaction was cooledand diluted with EtOAc then washed repeatedly with satd. NaHCO3 solutionuntil the washings were basic. The mixture was evaporated and the darkoil left to stand until crystallization was complete. The solidifiedmass was triturated with 8:2 AcCN:water then filtered and air-dried.There was obtained 1.38 g of pyrazole; mp 162.6° C.; LRMS (M+H)⁺m/z=376.

Preparation of ethyl3-methyl-1-(3-cyano-4-styrylphenyl)-1H-pyrazole-5-carboxylate

Ethyl 3-methyl-1-(3-amido-4-styrylphenyl)-1H-pyrazole-5-carboxylate(8.36 g, 22.3 mmol) in pyridine (50 mL) was cooled to 0° C. andmethanesulfonyl chloride (7.67 g, 66.9 mmol) added dropwise over 10 min.The ice bath was removed and the reaction left to stir for 18 h. Thereaction mixture was evaporated and the residue suspended in 1N HCl (200mL) and MeOH (60 mL). The mixture was stirred vigourously for 15 minthen filtered, washed with water and air-dried. There was obtained 6.23g of nitrile; mp 128.3° C.

Preparation of3-methyl-1-(3-cyano-4-styrylphenyl)-1H-pyrazole-5-carboxylic acid

The ethyl ester (7.17 g, 20 mmol) in MeOH (100 mL) with 50% NaOHsolution (10 mL) was stirred for 2 h at ambient temperature. After thistime TLC (2:1 EtOAc:Hexane) indicated that all of the starting ester wasconsumed. Water (100 mL) was added and the solution acidified (pH=1) bythe addition of conc. HCl. The percipitated product was removed byfiltration then washed with water and air-dried. There was obtained3-methyl-1-(3-cyano-4-styrylphenyl)-1H-pyrazole-5-carboxylic acid (5.9g); mp 225.9° C.

To 3-methyl-1-(3-cyano-4-styrylphenyl)-1H-pyrazole-5-carboxylic acid(5.6 g, 17 mmol) in CHCl3 (60 mL) and oxalyl chloride (3 mL) was added afew drops DMF. The reaction bubbled vigorously and after 20 min, whenthe reaction had subsided, the solvent was removed by distillation invacuo and pumped on for several hours to remove the last traces of HCl.Complete conversion to the acid chloride was demonstrated by TLC (2:1EtOAc:Hexane) by converting a small sample to the ethyl ester bytreatment with EtOH and comparison with a previously prepared sample.

To the acid chloride (17 mmol) in CHCl3 (100 mL) and pyridine (170 mmol)was added 4-(2′-N-t-butylsulfamido)phenyl)aniline (5.2 g, 17.1 mmol).The reaction was stirred for 1 h at ambient temperature, then dilutedwith 1:1 EtOAc:n-BuCl (300 mL) and washed with 1N HCl until washingswere acidic. The organic solution was dried and evaporated to give 8.12g of3-methyl-1-(3-cyano-4-styrylphenyl)-1H-pyrazole-5-(N-(4-(2′-t-butylsulfamido)phenyl)phenyl)carboxyamide;mp 130.3° C.; LRMS (M+Na)⁺ m/z=638.2.

Preparation of3-methyl-1-(3-cyano-4-formylphenyl)-1H-pyrazole-5-(N-(4-(2′-t-butylsulfamido)phenyl)phenyl)-carboxyamide

A MeOH (200 mL) solution of3-methyl-1-(3-cyano-4-styrylphenyl)-1H-pyrazole-5-(N-(4-(2′-t-butylsulfamido)phenyl)phenyl)carboxyamidewas cooled to −78° C. and saturated with a stream of ozone. The solutionwas then purged with a stream of N2 for 10 min and dimethylsulfide (3mL) added. The mixture was allowed to come to ambient temperature thanevaporated to dryness. The residue was dissolved in EtOAc, washed withwater (4×) dried (MgSO4) and evaporated. There was obtained 3.97 g ofthe aldehyde; LRMS (M+Na)⁺ m/z=564.0.

Preparation of Example 27

The above prepared carboxyamide (0.42 g, 0.78 mmol) with hydrazinehydrate (0.15 g, 3 mmol) and AcOH (0.28 g, 4.68 mmol) in benzene (25 mL)were heated at reflux under a Dean Stark trap for 18 h. The benzenesolution was cooled to ambient temperature and washed with water (3×)and dried (MgSO4) then evaporated. The residue was applied to a shortcolumn of flash silica and eluted with 1:1:0.078 EtOAc:Hexane:MeOH. Thedesired pthalazine product (0.1 g) was obtained in a mixture with3-methyl-1-(3-amido-4-(formylhydrazone)phenyl)-1H-pyrazole-5-(N-(4-(2′-t-butylsulfamido)phenyl)phenyl)carboxyamide.

This mixture was heated at reflux with trifluoroacetic acid (10 mL) for1 h, then evaporated. The mixture was separated by reverse phase hplc ona C18 column by eluting with a gradient of 20% AcCN:Water with 0.05% TFAto 100% AcCN with 0.05% TFA over 30 min. At 9.83 min3-methyl-1-(3-amido-4-(formylhydrazone)phenyl)-1H-pyrazole-5-(N-(4-(2′-sulfamido)phenyl)phenyl)carboxyamide(14 mg) was eluted; HRMS (M+H)⁺ found: 518.1634, calc.: 518.1610. At10.76 min the target compound, example 27 (2.8 mg) was eluted; HRMS(M+H)⁺ found: 500.1511, calc.: 500.1505.

Example 283-(3′-Aminobenzisoxazol-5′-yl)-5-[[5-[(2′-aminosulfonyl)phenyl]pyrid-2-yl]aminocarbonyl]-5-(methylsulfonylaminomethyl)isoxazolinePreparation of3-(3-cyano-4-fluorophenyl)-5-(azidomethyl)-5-(carbomethoxy)isoxazoline

3-Cyano-4-fluorobenzaldehyde (5.00 g) and hydroxyamine hydrochloride(2.90 g, 1.25 Eq) were dissolved in ethanol (100 mL) and pyridine (100mL). The mixture was stirred at RT under N₂ for 45 minutes. The solventswere removed and the brown oil was partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried over MgSO₄, andconcentrated to give 3-cyano-4-fluorobenzaldehydeoxime (5.03 g). CI massspectrum z (rel. intensity) 165 (M+H, 100).

Sodium azide (10.7 g) was added to a solution of methyl(2-bromomethyl)acrylate (20.0 g) in DMSO (200 mL). The mixture wasstirred at RT under N₂ for 2 h. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over MgSO₄, and concentrated to give methyl(2-azidomethyl)acrylate (14.1 g).

To a solution of 3-cyano-4-fluorobenzaldoxime (4.30 g) in CH₂Cl₂ (150mL) was added methyl (2-azidomethyl)acrylate (4.33 g). The mixture wascooled to 0° C. in an ice bath followed by dropwise addition of NaOCl(66 mL of 0.67 M aqueous solution) with vigorous stirring. After theaddition, the reaction mixture was slowly warmed up to RT (2 h). Themixture was washed with water and brine, dried over sodium sulfate, andconcentrated. The resulting solid was purified by chromatography onsilica gel with CH₂Cl₂ to give3-(3-cyano-4-fluorophenyl)-5-(azidomethyl)-5-(carbomethoxy)isoxazoline(2.45 g) as a pure compound. ¹H NMR (CDCl₃) δ 7.97 (m, 1H), 7.88 (m,1H), 7.31 (t, 1H), 3.87 (s, 3H), 3.87–3.46 (m, 4H) ppm; NH₃—CI massspectrum z (rel. intensity) 321 [(M+NH₄)⁺, 100].

Preparation of3-(3-cyano-4-fluorophenyl)-5-(aminomethyl)-5-(carbomethoxy)isoxazoline,hydrochloride salt

To a solution of3-[3-cyano-4-fluorophenyl]-5-(azidomethyl)-5-(carbomethoxy)isoxazoline(2.14 g) in THF (50 mL) was added triethylphosphite (1.45 mL). Themixture was refluxed under N₂ for 5 h. The THF was removed, and theresidue was dissolved in EtOAc and washed with water and brine. It wasdried over MgSO₄ and concentrated to a yellow oil. This oil was thendissolved in 4N HCl in dioxane (30 mL) and refluxed for 4 h. Thereaction mixture was cooled, and ether was added. The precipitate formedwas filtered and dried to give 1.15 g of the hydrochloride salt. ¹H NMR(DMSO) δ 8.36 (bs, 2H), 8.21 (m, 1H), 8.09 (m, 1H), 7.68 (t, 1H),4.02–3.80 (m, 2H), 3.78 (s, 3H), 3.70–3.37 (m, 2H) ppm; ESI massspectrum z (rel. intensity) 279.9 (M+H, 100).

Preparation of3-(3-cyano-4-fluorophenyl)-5-(methylsulfonylaminomethyl)-5-(carbomethoxy)isoxazoline

To a solution of3-(3-cyano-4-fluorophenyl)-5-(aminomethyl)-5-(carbomethoxy)isoxazolinehydrochloride salt (1.15 g) in CH₂Cl₂ (50 mL) was added triethylamine(1.27 mL) and methanesulfonyl chloride (0.31 mL). The mixture wasstirred at RT under N₂ for 1 h. The solvent was diluted with CH₂Cl₂ andwashed with water, 1N aqueous HCl, and saturated aqueous NaHCO₃. It wasdried over MgSO₄ and concentrated to a yellow solid (1.13 g). ¹H NMR(CDCl₃) δ 7.92 (m, 2H), 7.30 (t, 1H), 4.82 (t, 1H), 3.84 (s, 3H),3.76–3.60 (m, 4H), 3.03 (s, 3H) ppm; ESI mass spectrum z (rel.intensity) 377.9 (M+H, 100).

Preparation of3-(3-cyano-4-fluorophenyl)-5-(methylsulfonylaminomethyl)-5-(hydroxycarbonyl)isoxazoline

To a solution of3-(3-cyano-4-fluorophenyl)-5-(methylsulfonylaminomethyl)-5-(carbomethoxy)isoxazoline(1.13 g) in THF (50 mL) was added LiOH (3.50 mL of 1N aqueous solution).The mixture was stirred at RT under N₂ for ½ h. The solvent was removed,the resulting material was diluted with water and acidified withconcentrated HCl. It was then extracted with EtOAc, and the organicsolution was dried over MgSO₄ and concentrated to a light yellow foam(0.98 g). ¹H NMR (DMSO-d₆) δ 8.17 (m, 2H), 7.56 (t, 1H), 3.98–3.79 (m,2H), 3.69 (bs, 2H), 3.01 (s, 3H) ppm; ESI mass spectrum z (rel.intensity) 339.8 (M−H, 100).

Preparation of3-(3-cyano-4-fluorophenyl)-5-[[5-[(2′-t-butylaminosulfonyl)phenyl]pyrid-2-yl]aminocarbonyl]-5-(methylsulfonylaminomethyl)isoxazoline

To a solution of3-(3-cyano-4-fluorophenyl)-5-(methylsulfonylaminomethyl)-5-(hydroxycarbonyl)isoxazoline(0.33 g) in CH₃CN (15 mL) was added oxalyl chloride (0.22 mL), followedby a few drops of DMF. The mixture was refluxed under N₂ for 1 h. Thesolvent was removed, toluene was added and then removed to dryness. Theresulting solid was dried under vacuum. It was then dissolved in CH₂Cl₂(20 mL) and [2-(t-butylaminosulfonyl)phenyl]-2-aminopyridine (0.30 g)was added followed by DMAP (0.30 g). The resulting mixture was stirredat RT under N₂ for 16 h. It was diluted with CH₂Cl₂ and washed withwater and brine, dried over MgSO₄, and concentrated. The resulting solidwas purified by chromatography on silica gel with 1:1 EtOAc/CH₂Cl₂ togive 0.11 g of the desired product. ¹H NMR (CDCl₃) δ 9.43 (s, 1H), 8.40(d, 1H), 8.25 (d, 1H), 8.17 (dd, 1H), 7.98–7.83 (m, 3H), 7.62–7.50 (m,2H), 7.35–7.24 (m, 2H), 5.81 (t, 1H), 4.06 (s, 1H), 3.82 (m, 4H), 3.02(s, 3H), 1.07 (s, 9H) ppm; ESI mass spectrum z (rel. intensity) 629.0(M+H, 100).

Preparation of3-(3′-Aminobenzisoxazol-5′-yl)-5-[[5-[(2′-aminosulfonyl)phenyl]pyrid-2-yl]aminocarbonyl]-5-(methylsulfonylaminomethyl)isoxazoline

To a solution of acetone oxime (28.0 mg) in DMF (2 mL) was addedpotassium tert-butoxide (1.0 M in THF, 0.44 mL) via syringe. The mixturewas stirred at RT for 15 minutes, a solution of3-(3-cyano-4-fluorophenyl)-5-[[5-[(2′-t-butylaminosulfonyl)phenyl]pyrid-2-yl]aminocarbonyl]-5-(methylsulfonylaminomethyl)isoxazoline(0.16 g) in DMF (2 mL) was added. The reaction mixture was stirred at RTovernight. Aqueous NH₄Cl was added to quench the reaction solution. Themixture was poured into water and extracted with EtOAc. The organicsolution was washed with brine, dried over MgSO₄, and concentrated to anoil.

This oil was dissolved in ethanol (8 mL) and methanol (2 mL). AqueousHCl (18%, 2 mL) was added. The mixture was heated at 80° C. for 2 h. Thesolvents were removed and the residue was dissolved in CH₃CN andpurified by HPLC (C18 reverse phase, eluted with 0.05% of TFA inH₂O/CH₃CN) to give 50 mg of white solid as TFA salt. ESI mass spectrum z(rel. intensity) 641.9 (M+H, 100).

The above solid was refluxed with 5 mL of TFA under N₂ for ½ h. Thesolvents were removed and the residue was dissolved in CH₃CN andpurified by HPLC (C18 reverse phase, eluted with 0.05% of TFA inH₂O/CH₃CN) to give 31 mg of white solid as TFA salt. ¹H NMR (DMSO-d₆) δ9.43 (s, 1H), 8.40 (d, 1H), 9.82 (s, 1H), 8.34 (d, 1H), 8.25 (s, 1H),8.12–8.02 (m, 2H), 7.95–7.84 (m, 2H), 7.70–7.51 (m, 2H), 7.38 (m, 2H),3.98–3.50 (m, 4H), 2.98 (s, 3H) ppm. ESI mass spectrum z (rel.intensity) 585.8 (M+H, 100).

Example 291-(33-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(2-fluoro-4-morpholinophenyl)aminocarbonyl]pyrazolePreparation of 2-fluoro-4-morpholinoaniline

A solution of 2,4-difluoronitrobenzene (10.0 mL) and morpholine (17.4mL) in THF (100 mL) was stirred at RT under N₂ for 2 h. The solvent wasremoved and the residue was partitioned between EtOAc and water. Theorganic layer was washed brine, dried over MgSO₄, and concentrated. Theresulting solid was purified by chromatography on silica gel with 20–50%EtOAc in hexane to give 18.1 g of 4-fluoro-2-morpholinonitrobenzene and1.81 g of 2-fluoro-4-morpholinonitrobenzene. ESI mass spectrum z (rel.intensity) 227.1 (M+H, 100).

2-Fluoro-4-morpholinonitrobenzene (1.80 g) was dissolved in methanol(100 mL) and 10% Pd/C (94 mg) was added. The mixture was placed in ahydrogenator (45 psi) for 2.5 h. The reaction mixture was filteredthrough celite and washed with methanol. The filtrate was concentratedto give 1.51 g solid. ¹H NMR (CDCl₃) δ 6.76–6.54 (m, 3H), 3.84 (t, 4H),3.45 (bs, 2H), 3.02 (t, 4H) ppm. ESI mass spectrum z (rel. intensity)197.1 (M+H, 100).

Preparation of1-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-4-morpholinophenyl)-aminocarbonyl]pyrazole

The title compound was prepared from1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-pyrazolecarboxylic acidand 2-fluoro-4-morpholinoaniline as a TFA salt by the same proceduresdescribed in Example 26. ¹H NMR (DMSO-d₆) δ 9.39 (s, 1H), 8.06 (d, 1H),7.77–7.48 (m, 4H), 6.81–6.75 (m, 2H), 3.77 (t, 4H), 3.15 (t, 4H) ppm.ESI mass spectrum z (rel. intensity) 491.2 (M+H, 100).

Example 301-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-(2′-isopropylimidazol-1′-yl)phenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (DMSO-d₆) δ 10.03 (s, 1H), 8.08 (d, 1H), 8.00 (d, 2H), 7.79–7.56 (m,7H), 3.28 (m, 1H), 1.39 (d, 6H) ppm. ESI mass spectrum z (rel.intensity) 496.3 (M+H, 100).

Example 311-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-(2′-ethylimidazol-1′-yl)phenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (DMSO-d₆) δ 10.48 (s, 1H), 8.08 (d, 1H), 8.00 (d, 2H), 7.79–7.56 (m,7H), 3.00 (q, 2H), 1.29 (t, 3H) ppm. ESI mass spectrum z (rel.intensity) 482.2 (M+H, 100).

Example 321-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-[(2′-dimethylaminomethyl)imidazol-1′-yl]phenyl]aminocarbonyl]pyrazolePreparation of 4-[(2′-dimethylaminomethyl)imidazol-1′-yl]aniline

To a solution of 4-fluoronitrobenzene (7.87 g) and2-imidazole-carboxaldehyde (5.90 g) in DMF (60 mL) was added K₂CO₃ (9.26g). The mixture was heated at 80° C. under N₂ for 16 h. The mixture waspoured into water, and the precipitate was filtered to give 6.70 g ofyellow solid. The filtrate was then extracted with EtOAc, and theorganic layer was washed brine, dried over MgSO₄, and concentrated to ayellow solid (5.40 g). Both batch were identified as the4-[(2′-carboxaldehyde)imidazol-1′-yl]nitrobenzene. ESI mass spectrum z(rel. intensity) 218 (M+H, 100).

A mixture of 4-[(2′-carboxaldehyde)imidazol-1′-yl]nitrobenzene (3.00 g)and dimethylamine (32 mL of 40% aqueous solution) in methanol (50 mL)was stirred at RT under N₂ for ½ h. NaBH₄ (1.56 g) was added portionwise. After the addition was completed, the reaction mixture was heatedat 56° C. for 2 h. Brine was added to the reaction mixture, it was thenextracted with CH₂Cl₂. The organic solution was washed with brine, driedover MgSO₄, and concentrated to give 1.96 g of4-[(2′-dimethylaminomethyl)imidazol-1′-yl]nitrobenzene. ESI massspectrum z (rel. intensity) 247.2 (M+H, 100).

4-[(2′-dimethylaminomethyl)imidazol-1′-yl]nitrobenzene (1.96 g) wasdissolved in methanol (100 mL) and 10% Pd/C (0.20 g) was added. Themixture was placed in a hydrogenator (30 psi) for 12 h. The reactionmixture was filtered through celite and washed with methanol. Thefiltrate was concentrated. It was then purified by chromatography onsilica gel with 20% methanol in CH₂Cl₂ to give 1.30 g of4-[(2′-dimethylaminomethyl)imidazol-1′-yl]aniline. ¹H NMR (CDCl₃) δ 7.25(dd, 2H), 7.03 (d, 2H), 6.72 (d, 2H), 3.82 (bs, 2H), 3.36 (s, 2H), 2.24(s, 6H) ppm. ESI mass spectrum z (rel. intensity) 217.2 (M+H, 100).

Preparation of1-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-[(2′-dimethylaminomethyl)imidazol-1′-yl]phenyl]aminocarbonyl]pyrazole

The title compound was prepared from1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-pyrazolecarboxylic acidand 4-[(2′-dimethylaminomethyl)imidazol-1′-yl]aniline as a TFA salt bythe same procedures described in Example 26. ¹H NMR (acetone-d₆) δ 10.39(s, 1H), 8.07 (d, 1H), 7.93 (d, 2H), 7.76 (m, 1H), 7.56 (m, 5H), 7.36(d, 1H), 4.59 (s, 2H), 3.00 (s, 6H), ppm. ESI mass spectrum z (rel.intensity) 511.2 (M+H, 100).

Example 331-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-[(2′-methoxymethyl)imidazol-1′-yl]phenyl]aminocarbonyl]pyrazolePreparation of 4-(2′-methoxymethyl)imidazol-1′-yl]aniline

4-[(2′-Carboxaldehyde)imidazol-1′-yl]nitrobenzene (3.00 g) was dissolvedin methanol (50 mL). NaBH₄ (1.56 g) was added portion wise. After theaddition was completed, the reaction mixture was stirred at RT under N₂for 12 h. The methanol was removed and water was added. The precipitateformed was filtered and dried to give 1.90 g of4-[(2′-hydroxymethyl)imidazol-1′-yl]nitrobenzene. ¹H NMR (DMSO-d₆) δ8.39 (d, 2H), 7.91 (d, 2H), 7.58 (s, 1H), 7.06 (s, 1H), 5.60 (t, 1H),4.48 (d, 2H). AP mass spectrum z (rel. intensity) 220.1 (M+H, 100).

4-[(2′-hydroxymethyl)imidazol-1′-yl]nitrobenzene (1.70 g) was dissolvedin CH₂Cl₂. Triethylamine (1.62 mL) was added followed by methanesulfonylchloride (0.76 mL). The mixture was stirred at RT under N₂ for 2.5 h.The solvent was removed. The residue was dissolved in methanol (100 mL)and NaOMe (10 mL of 20% solution in methanol) was added. The reactionmixture was stirred at RT under N₂ for 12 h. The solvent was removed.The residue was partitioned between water and CH₂Cl₂. The organicsolution was washed with brine, dried over MgSO₄, and concentrated togive 1.60 g of 4-[(2′-methoxymethyl)imidazol-1′-yl]nitrobenzene. ¹H NMR(CDCl₃) δ 8.39 (d, 2H), 7.72 (d, 2H), 7.20 (s, 2H), 4.45 (s, 2H), 3.42(s, 3H). ESI mass spectrum z (rel. intensity) 234.1 (M+H, 100).

4-[(2′-Methoxymethyl)imidazol-1′-yl]nitrobenzene (1.78 g) was dissolvedin methanol (100 mL) and 10% Pd/C (0.20 g) was added. The mixture wasplaced in a hydrogenator (40 psi) for 20 h. The reaction mixture wasfiltered through celite and washed with methanol. The filtrate wasconcentrated. It was then purified by chromatography on silica gel with5% methanol in CH₂Cl₂ to give 0.67 g of4-[(2′-methoxymethyl)imidazol-1′-yl]aniline. ¹H NMR (CDCl₃) δ 7.18 (d,2H), 7.06 (d, 2H), 6.71 (d, 2H), 4.36 (s, 2H), 3.96 (bs, 2H), 3.35 (s,3H) ppm. ESI mass spectrum z (rel. intensity) 204.2 (M+H, 100).

Preparation of1-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-[(2′-methoxymethyl)imidazol-1′-yl]phenyl]aminocarbonyl]pyrazole

The title compound was prepared from1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-pyrazolecarboxylic acidand 4-[(2′-methoxymethyl)imidazol-1′-yl]aniline as a TFA salt by thesame procedures described in Example 26. ¹H NMR (acetone-d₆) δ 10.39 (s,1H), 8.08 (d, 1H), 7.97 (d, 2H), 7.76 (m, 2H), 7.69 (m, 3H), 7.57 (m,2H), 4.75 (s, 2H), 3.36 (s, 3H), ppm. ESI mass spectrum z (rel.intensity) 498.2 (M+H, 100).

Example 34 1-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-[(2′-dimethylaminomethyl)imidazol-1′-yl]-2-fluorophenyl]aminocarbonyl]pyrazolePreparation of4-[(2′-dimethylaminomethyl)imidazol-1′-yl]-2-fluoroaniline

2-Imidazole-carboxaldehyde (1.00 g) and dimethylamine (10 mL of 40%aqueous solution) in methanol (10 mL) was stirred at RT under N₂ for ½h. NaBH₄ (1.18 g) was added portion wise. After the addition wascompleted, the reaction mixture was heated at 56° C. for 2 h. Brine wasadded to the reaction mixture, it was then extracted with CH₂Cl₂. Theorganic solution was washed with brine, dried over MgSO₄, andconcentrated to 2-(dimethylaminomethyl)imidazole as a yellow oil. ¹H NMR(CDCl₃) δ 6.97 (s, 2H), 3.61 (s, 2H), 2.28 (s, 6H) ppm.

The above oil was dissolved in DMF (10 mL) and KO-t-Bu (10.5 mL of 1Msolution in THF) was added. The mixture was stirred at RT under N₂ for ½h. It was then added dropwise to a solution of 2,4-difluoronitrobenzene(1.14 mL) in DMF (10 mL). The resulting mixture was stirred at RT underN₂ for 2 h. The mixture was poured into water and extracted with EtOAc.The organic layer was washed brine, dried over MgSO₄, and concentratedto a yellow oil. The resulting material was purified by chromatographyon silica gel with EtOAc to give 1.11 g of a 1:5 mixture of2-fluoro-4-[(2′-dimethylaminomethyl)imidazol-1′-yl]nitrobenzene and4-fluoro-2-[(2′-dimethylaminomethyl)imidazol-1′-yl]nitrobenzene. ESImass spectrum z (rel. intensity) 265.2 (M+H, 100).

The above mixture was dissolved in methanol (100 mL) and 10% Pd/C (0.15g) was added. The mixture was placed in a hydrogenator (40 psi) for 8 h.The reaction mixture was filtered through celite and washed withmethanol. The filtrate was concentrated. The two regioisomers were thenseparated by HPLC (C18 reverse phase, eluted with 0.05% TFA inH₂O/CH₃CN) to give 80 mg of4-[(2′-dimethylaminomethyl)imidazol-1′-yl]-2-fluoroaniline and 0.48 g of2-[(2′-dimethylaminomethyl)imidazol-1′-yl]-4-fluoroaniline. ESI massspectrum z (rel. intensity) 235.2 (M+H, 100).

Preparation of1-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-[(2′-dimethylaminomethyl)imidazol-1′-yl]phenyl]aminocarbonyl]pyrazole

The title compound was prepared from1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-pyrazolecarboxylic acidand 4-[(2′-dimethylaminomethyl)imidazol-1′-yl]-2-fluoroaniline as a TFAsalt by the same procedures described in Example 26. ¹H NMR (acetone-d₆)δ 9.95 (s, 1H), 8.20–8.09 (m, 2H), 7.78 (m, 1H), 7.59 (m, 4H), 7.44 (d,1H), 7.36 (d, 1H), 4.68 (s, 2H), 3.05 (s, 6H), ppm. ESI mass spectrum z(rel. intensity) 529.2 (M+H, 100).

Example 351-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[(2-methoxy-4-(2′-methylimidazol-1′-yl)phenyl]aminocarbonyl]pyrazolePreparation of 2-methoxy-4-(2′-methylimidazol-1′-yl)aniline

A solution of 5-fluoro-2-nitrophenol (2.03 g) and 2-methylimidazole(2.14 g) in CH₃CN (50 mL) was stirred at reflux under N₂ for 16 h. Thesolvent was removed and the residue was purified by chromatography onsilica gel with 0–10% MeOH in CH₂Cl₂ to give 2.21 g of5-(2′-methylimdazol-1-yl)-2-nitrophenol. ESI mass spectrum z (rel.intensity) 220.1 (M+H, 100).

5-(2′-Methylimdazol-1-yl)-2-nitrophenol (1.16 g) was dissolved in DMF(30 mL). To this solution was added K₂CO₃ (0.92 g) and iodomethane (0.33mL) and the reaction mixture was stirred at RT under N₂ for 6 h. Thereaction mixture was poured into 100 mL water and extracted with EtOAc(4×50 mL), dried over MgSO₄, and concentrated to give 0.25 g of2-methoxy-4-(2′-methylimidazol-1′-yl)nitrobenzene. ESI mass spectrum z(rel. intensity) 234.2 (M+H, 100).

2-Methoxy-4-(2′-methylimidazol-1′-yl)nitrobenzene (0.25 g) was dissolvedin methanol (20 mL) and 10% Pd/C (29.3 mg) was added. The mixture wasplaced on a hydrogenator (40 psi) for 4 h. The reaction mixture wasfiltered and washed with methanol. The filtrate was concentrated to give0.27 g of the title compound. ¹H NMR (CDCl₃) δ 2.32 (s, 3H, CH₃), 3.86(s, 3H, OCH₃), 3.95 (bs, 2H, NH₂), 6.68 (t, 1H, J=1.8 Hz, aromatic H),6.72 (m, 2H, aromatic H), 6.95 (d, 1H, J=1.4 Hz, imidazole H), 6.99 (d,1H, J=1.1 Hz, imidazole H) ppm. ESI mass spectrum z (rel. intensity)204.2 (M+H, 100).

Preparation of1-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[(2′-methoxy-4-(2′-methylimidazol-1′-yl)phenyl]aminocarbonyl]pyrazole

The title compound was prepared from1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-pyrazolecarboxylic acidand 2-methoxy-4-(2′-methylimidazol-1′-yl)aniline as a TFA salt by theprocedures described in Example 26. ¹H NMR (DMSO) δ 2.53 (s, 3H, CH₃),3.82 (s, 3H, OCH₃), 7.17 (dd, 1H, J=10.0 Hz, J=1.5 Hz, aromatic H), 7.35(d, 1H J=1.4, aromatic H), 7.58 (d, 1H, J=8.8, aromatic H), 7.60 (s, 1H,pyrazole H), 7.65 (d, 1H, J=1.5, aromatic H), 7.76 (d, 1H, J=1.8,imidazole H), 7.87 (d, 1H, J=1.8, imidazole H), 7.90 (bs, 1H, NH), 8.11(d, 1H J=1.4, aromatic H), 10.15 (bs, 1H, CF₃CO₂H) ppm. ESI massspectrum z (rel. intensity) 498.3 (M+H, 100).

Example 361-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-(2′-isopropylimidazol-1′-yl)-2-fluorophenyl]amino-carbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 10.02 (s, 1H), 8.28 (t, 1H), 8.11 (d, 1H), 7.82–7.56(m, 7H), 3.33 (m, 1H), 1.40 (d, 6H) ppm. ESI mass spectrum z (rel.intensity) 514.2 (M+H, 100).

Example 371-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[[4-(2′-ethylimidazol-1′-yl)-2-fluorophenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 9.99 (s, 1H), 8.27 (t, 1H), 8.10 (d, 1H), 7.80–7.57(m, 7H), 3.04 (q, 2H), 1.30 (t, 3H) ppm. ESI mass spectrum z (rel.intensity) 500.2 (M+H, 100).

Example 381-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[4-(2′-ethylimidazol-1′-yl)-2-fluorophenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 9.63 (S, 1H), 8.28 (t, 1H), 7.98 (d, 1H), 7.72–7.48(m, 6H), 7.03 (s, 1H), 3.04 (q, 2H), 2.73 (q, 2H), 1.31 (tt, 6H) ppm.ESI mass spectrum z (rel. intensity) 460.2 (M+H, 100).

Example 391-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[4-[(2′-methoxymethyl)imidazol-1′-yl]phenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (DMSO) δ 10.82 (s, 1H), 8.02–7.75 (m, 5H), 7.62–7.48 (m, 4H), 7.04(s, 1H), 4.59 (s, 2H), 3.30 (s, 3H) ppm. ESI mass spectrum z (rel.intensity) 458.3 (M+H, 100).

Example 401-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[4-[(2′-dimethylaminomethyl)imidazol-1′-yl]phenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (CD₃OD) δ 7.89 (d, 1H), 7.82 (d, 2H), 7.58 (dd, 2H), 7.50–7.48 (m,3H), 7.28 (d, 5H), 6.96 (s, 1H), 4.35 (s, 2H), 2.81 (s, 6H), 2.78 (q,2H), 1.37 (t, 3H) ppm. ESI mass spectrum z (rel. intensity) 471.3 (M+H,100).

Example 411-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[4-[(2′-methyl)benzimidazol-1′-yl]phenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 10.10 (s, 1H), 8.09 (d, 2H), 7.99 (d, 1H), 7.93 (d,1H), 7.76–7.67 (m, 3H), 7.57–7.30 (m, 5H), 7.00 (s, 1H), 2.76 (q, 2H),1.31 (t, 3H) ppm. ESI mass spectrum z (rel. intensity) 478.2 (M+H, 100).

Example 421-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[(2′-ethylimidazol-1′-ylphenyl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 10.10 (s, 1H), 7.98 (m, 3H), 7.64 (m, 5H), 7.50 (d,1H), 6.98 (s, 1H), 3.02 (q, 2H), 2.75 (q, 2H), 1.30 (tt, 6H) ppm. ESImass spectrum z (rel. intensity) 442.2 (M+H, 100).

Example 431-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[4-(2′-ethylimidazol-1′-yl)-2,5-difluorophenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 9.80 (s, 1H), 8.30–8.24 (m, 1H), 7.99 (d, 1H),7.85–7.63 (m, 4H), 7.51 (d, 1H), 7.06 (s, 1H), 4.40 (bs, 2H), 2.70 (q,2H), 2.68 (s, 3H), 1.26 (t, 3H) ppm. ESI mass spectrum z (rel.intensity) 464.2 (M+H, 100).

Example 441-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[(2-fluoro-4-morpholinophenyl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 9.08 (s, 1H), 7.94 (d, 1H), 7.64 (m, 2H), 7.47 (d,1H), 6.92 (s, 1H), 6.78 (m, 2H), 4.07 (bs, 2H), 3.77 (t, 4H), 3.14 (t,4H), 2.70 (q, 2H), 1.28 (t, 3H) ppm. ESI mass spectrum z (rel.intensity) 451.2 (M+H, 100).

Example 451-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[(2′-isopropylimidazol-1′-ylphenyl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 10.15 (s, 1H), 7.98 (m, 3H), 7.70–7.59 (m, 5H), 7.48(d, 1H), 6.99 (s, 1H), 3.26 (m, 1H), 2.74 (q, 2H), 1.39 (d, 6H), 1.30(t, 3H) ppm. ESI mass spectrum z (rel. intensity) 456.3 (M+H, 100).

Example 461-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[4-(2′-methylimidazol-1′-yl)-2-fluorophenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 9.67 (s, 1H), 8.25 (t, 1H), 7.98 (dd, 1H), 7.71–7.48(m, 6H), 7.04 (s, 1H), 2.72 (q, 2H), 2.69 (s, 3H), 1.31 (t, 3H) ppm. ESImass spectrum z (rel. intensity) 446.2 (M+H, 100).

Example 471-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[(2′-aminosulfonyl-3-amino-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (DMSO-d₆) δ 10.02 (s, 1H), 8.01 (d, 1H), 7.99 (s, 1H), 7.58 (m, 3H),7.49 (t, 1H), 7.26 (tt, 2H), 7.17 (s, 1H), 7.06 (s, 1H), 6.91 (s, 1H),6.82 (d, 1H), 2.71 (q, 2H), 1.28 (t, 3H) ppm. ESI mass spectrum z (rel.intensity) 540.2 (M+Na, 100).

Example 481-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[(2′-aminosulfonyl-3-nitro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (DMSO-d₆) δ 10.91 (s, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.70 (s, 1H),7.62 (m, 2H), 7.47 (m, 4H), 7.36 (m, 2H), 7.04 (s, 1H), 6.50 (bs, 2H),2.71 (q, 2H), 1.25 (t, 3H) ppm. ESI mass spectrum z (rel. intensity)548.2 (M+H, 100).

Example 491-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[4-(2′-methylimidazol-1′-yl)phenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 10.13 (s, 1H), 8.00–7.95 (m, 3H), 7.68–7.61 (m, 5H),7.48 (d, 1H), 6.99 (s, 1H), 2.74 (q, 2H), 2.67 (s, 3H), 1.29 (t, 3H)ppm. ESI mass spectrum z (rel. intensity) 428.2 (M+H, 100).

Example 501-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[2-dimethyl-4-(N-pyrrolidinocarbonyl)phenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (acetone-d₆) δ 9.31 (bs, 1H), 8.27 (d, 1H), 7.99 (d, 1H), 7.72 (dd,1H), 7.51 (m, 2H), 7.36 (d, 1H), 6.94 (s, 1H), 4.70 (bs, 2H), 3.53 (bs,4H), 2.73 (q, 2H), 2.62 (s, 6H), 1.92 (bs, 4H), 1.30 (t, 3H) ppm. ESImass spectrum z (rel. intensity) 488.0 (M+H, 100).

Example 511-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[2-pyrrolidino-4-(N-pyrrolidinocarbonyl)phenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (DMSO-d₆) δ 9.90 (s, 1H), 7.90 (s, 1H), 7.46 (m, 2H), 7.18 (d, 1H),6.93 (s, 1H), 6.83 (m, 2H), 3.38 (m, 4H), 3.19 (bs, 4H), 2.64 (q, 2H),1.78 (m, 8H), 1.24 (t, 3H) ppm. ESI mass spectrum z (rel. intensity)513.9 (M+H, 100).

Example 521-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (CDCl₃) δ 8.35 (m, 1H), 8.06 (m, 1H), 7.68 (s, 1H), 7.57 (dd, 1H),7.43 (d, 1H), 7.25 (m, 2H), 6.85 (s, 1H), 4.64 (bs, 2H), 3.61 (t, 2H),3.40 (t, 2H), 2.76 (q, 2H), 1.90 (m, 4H), 1.28 (t, 3H) ppm. ESI massspectrum z (rel. intensity) 463.0 (M+H, 100).

Example 531-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (DMSO-d₆) δ 10.32 (s, 1H), 8.01–7.94 (m, 2H), 7.63–7.44 (m, 5H),7.40–7.23 (m, 4H), 7.15 (dd, 1H), 7.01 (s, 1H), 2.67 (q, 2H), 1.25 (t,3H) ppm. ESI mass spectrum z (rel. intensity) 542.9 (M+Na, 100).

Example 541-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[5-[(2′-methylsulfonyl)phenyl]pyrimid-2-yl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (DMSO-d₆) δ 11.34 (s, 1H), 8.68 (s, 2H), 8.13 (dd, 1H), 7.96 (d,1H), 7.80 (m, 2H), 7.64 (m, 2H), 7.10 (s, 1H), 3.05 (s, 3H), 2.70 (q,2H) 1.29 (t, 3H) ppm. ESI mass spectrum z (rel. intensity) 525.9 (M+Na,100).

Example 551-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as TFA salt. ¹HNMR (DMSO-d₆) δ 10.33 (s, 1H), 8.07 (d, 1H), 7.96 (s, 1H), 7.78–7.61 (m,3H), 7.55–7.47 (m, 2H), 7.41 (d, 1H), 7.21 (s, 1H), 7.04 (s, 1H), 2.90(s, 3H), 2.70 (q, 2H), 1.28 (t, 3H) ppm. ESI mass spectrum z (rel.intensity) 541.9 (M+Na, 100).

Example 561-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[[5-[(2′-aminosulfonyl)phenyl]pyrid-2-yl]aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion as mesylatesalt. ¹H NMR (CD₃OD) δ 8.51 (dd, 1H), 8.36 (d, 1H), 8.15 (d, 1H), 7.93(d, 1H), 7.81 (d, 1H), 7.70 (m, 3H), 7.48 (m, 2H), 7.32 (s, 1H), 2.83(q, 2H), 1.39 (t, 3H) ppm. ESI mass spectrum z (rel. intensity) 502.0(M−H, 100).

Example 571-(3′-Aminobenzisoxazol-5′-yl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]tetrazolePreparation of ethyl 1-(3-cyano-4-fluorophenyl)-5-tetrazole carboxylate

To a suspension of 2-fluoro-5-nitrobenzonitrile (5.20 g) in ethanol (150mL) was added 5% Pd/C (1.00 g). The reaction was placed on ahydrogenator (50 psi) for 10 minutes. The reaction mixture was filteredthrough celite and the filtrate evaporated to give 4.25 g of5-amino-2-fluorobenzonitrile. ¹H NMR (CDCl₃) δ 3.75 (bs, 2H, NH₂), 6.83(m, 2H, aromatic H), 6.99 (m, 1H, aromatic H). GC mass spectrum z (rel.intensity) 137 (M+H, 100).

To a solution of 5-amino-2-fluorobenzonitrile (3.75 g) and Et₃N (4.22mL) in CH₂Cl₂ (100 mL) was added ethyloxalyl chloride (3.08 mL) in adropwise fashion over 10 minutes. The reaction was stirred at RT underN₂ for 1.5 h. The reaction mixture was washed with water (2×50 mL) andbrine (1×50 mL), filtered through phase separatory paper and evaporated.The residue was dissolved in 20 mL of CH₂Cl₂ and 100 mL of hexane wasadded. The solution was allowed to stand at RT for the weekend. Theprecipitate was filtered, rinsed with hexane, and dried under vacuum togive 5.43 g of 1-(3-cyano-4-fluorophenyl)-oxoacetic acid ethyl ester. ¹HNMR (CDCl₃) δ 1.44 (t, 3H, J=7.2 Hz, OCH₂CH₃), 4.44 (q, 2H, J=7.0 Hz,OCH₂CH₃), 7.26 (t, 1H, J=3.8 Hz, aromatic H), 7.82 (m, 1H, aromatic H),8.04 (m, 1H, aromatic H), 8.97 (bs, 1H, NH). DCI mass spectrum z (rel.intensity) 237.1 (M+H, 6.6), 254.0 (M+Na, 100).

A solution of triphenylphosphine (10.89 g) in CCl₄ (100 mL) was stirredat 0° C. for 30 minutes. 1-(3-Cyano-4-fluorophenyl)-oxoacetic acid ethylester (4.86 g) in CCl₄ (50 mL) was added and the reaction was stirred atreflux under N₂ for 16 h. The reaction was cooled to RT and theprecipitate was filtered off. The filtrate was evaporated and dissolvedin CH₃CN (200 mL). Sodium azide (1.34 g) was added and the reactionstirred at RT under N₂ for 16 h. The solvent was evaporated and theresidue was taken up in EtOAc (100 mL). The organic solution was washedwith water (2×50 mL) and brine (1×50 mL), dried over MgSO₄, andevaporated. The crude material was purified by silica gel chromatographyeluting with CH₂Cl₂ to give 1.85 g of the title compound. ¹H NMR (CDCl₃)δ 1.44 (t, 3H, J=7.1 Hz, OCH₂CH₃), 4.50 (q, 2H, J=7.1 Hz, OCH₂CH₃), 7.47(t, 1H, J=3.8 Hz, aromatic H), 7.81 (m, 1H, aromatic H), 7.87 (m, 1H,aromatic H).

Preparation of1-(3′-Aminobenzisoxazol-5′-yl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]tetrazole

To a solution of[(2′-methylaminosulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]amine (0.23 g) inanhydrous CH₂Cl₂ (15 mL) was added trimethylaluminum (1.60 mL, 2M inheptane). The reaction was stirred at RT under N₂ for 15 minutes. Asolution of ethyl 1-(3-cyano-4-fluorophenyl)-5-tetrazole carboxylate(0.20 g) in anhydrous CH₂Cl₂ (10 mL) was added and the reaction wasstirred at RT under N₂ for 16 h. The reaction was quenched with 5 mL of1N HCl and diluted with CH₂Cl₂ (30 mL). The organic solution was washedwith water (2×25 mL) and brine (1×25 mL), filtered through phaseseparatory paper, and evaporated to give 0.21 g of1-(3′-cyano-4′-fluorophenyl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]tetrazole.ESI mass spectrum z (rel. intensity) 479.1 (M−H, 100).

To a solution of acetone oxime (59.3 mg) in 5 mL of anhydrous DMF wasadded potassium tert-butoxide (1.20 mL, 1M in THF) and the mixturestirred at RT under N₂ for 15 minutes. A solution of1-(3′-cyano-4′-fluorophenyl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]tetrazole(0.19 g) in 10 mL of anhydrous DMF was added and the reaction wasstirred at RT under N₂ for 16 h. The reaction was quenched withsaturated aqueous NH₄Cl, poured into 50 mL of water, and extracted withEtOAc (3×50 mL). The combined organic solution was washed with water(2×25 mL) and brine (1×25 mL), dried over MgSO₄, and evaporated. Thecrude material was purified by silica gel chromatography eluting with 2%MeOH in CH₂Cl₂ to give 0.11 g of a white solid. To a suspension of thissolid (0.10 g) in 10 mL of EtOH was added 4 mL of 18% aqueous HCl. Thesolution was stirred at 80° C. under N₂ for 1 h, then cooled to RT. Theresulting precipitate was filtered and dried under vacuum to give 71.7mg of1-(3′-Aminobenzisoxazol-5′-yl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]tetrazole.¹H NMR (DMSO-d₆) δ 2.93 (s, 3H, CH₃), 6.66 (bs, 2H, NH₂), 7.25 (d, 1H,J=9.8 Hz, aromatic H), 7.41 (t, 2H, J=8.0 Hz, aromatic H), 7.70 (m, 3H,aromatic H), 7.77 (t, 1H, J=6.2 Hz, aromatic H), 7.89 (d, 1H, J=9.0 Hz,aromatic H), 8.09 (d, 1H, J=6.6 Hz, aromatic H), 8.20 (s, 1H, aromaticH), 11.26 (s, 1H, NH). ESI mass spectrum z (rel. intensity) 492.1 (M−H,100).

1-(3′-Aminobenzisoxazol-5′-yl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]tetrazole(58.2 mg) was dissolved in 20 mL of MeOH and a solution ofmethanesulfonic acid (1.18 mL, 0.1M in THF) was added. The reaction wasstirred at RT under N₂ for 2 h and evaporated. The residue was dissolvedin water and evaporated to give 55.6 mg of the title compound as themesylate salt. ¹H NMR (DMSO-d₆) δ 2.37 (s, 3H, CH ₃SO₃H), 2.93 (s, 3H,CH₃), 7.26 (d, 1H, J=7.6 Hz, aromatic H), 7.40 (d, 1H, J=9.2 Hz,aromatic H), 7.42 (d, 1H, J=11.1 Hz, aromatic H), 7.72 (m, 3H, aromaticH), 7.78 (m, 1 H, aromatic H), 7.89 (dd, 1H, J=9.0 Hz, J=2.0 Hz,aromatic H), 8.10 (d, 1H, J=7.9 Hz, aromatic H), 8.21 (d, 1H, J=1.9 Hz,aromatic H), 11.27 (s, 1H, CH₃SO₃H). APCI mass spectrum z 494.1 (M+H).HRMS (Q-TOF) calc. 494.104677, obs. 494.105900.

Example 581-(3′-Aminobenzisoxazol-5′-yl)-5-[[4-(2′-methylimidazol-1′-yl)phenyl]aminocarbonyl]tetrazole

The title compound was prepared in an analogous fashion as the TFA salt.¹H NMR (DMSO-d₆) δ 6.65 (bs, 2H, NH₂, 7.62 (d, 2H, J=9.1 Hz, aromaticH), 7.70 (d, 1H, J=8.8 Hz, aromatic H), 7.75 (d, 1H, J=2.2 Hz, aromaticH), 7.86 (d, 1 H, J=2.2 Hz, imidazole H), 7.93 (dd, 1H, J=9.0 Hz, J=2.0Hz, imidazole H), 8.00 (d, 2H, J=9.1 Hz, aromatic H), 8.19 (d, 1H, J=2.2Hz, aromatic H), 11.72 (s, 1H, CF₃CO₂H) ESI mass spectrum z (rel.intensity) 402.2 (M+H, 100).

Example 591-(3′-Aminobenzisoxazol-5′-yl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]tetrazole

The title compound was prepared in an analogous fashion as the TFA salt.¹H NMR (DMSO-d₆) δ 6.65 (bs, 2H, NH₂), 7.27 (bs, 2H, NH₂), 7.30 (d, 1H,J=7.3 Hz, aromatic H), 7.38 (d, 2H, J=8.4 Hz, aromatic H), 7.59 (m, 2H,aromatic H), 7.71 (d, 1H, J=9.1 Hz, aromatic H), 7.77 (d, 2H, J=8.4 Hz,aromatic H), 7.90 (d, 1H, J=8.8 Hz, aromatic H), 8.20 (s, 1H, aromaticH), 11.49 (s, 1H, CF₃CO₂H). ESI mass spectrum z (rel. intensity) 474.9(M−H, 100).

Example 601-(3′-Aminobenzisoxazol-5′-yl)-5-[(2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]tetrazole

The title compound was prepared in an analogous fashion as the TFA salt.¹H NMR (DMSO-d₆) δ 1.83 (m, 4H, CH₂), 3.39 (t, 2H, J=6.2 Hz, CH₂), 3.45(t, 2H, J=6.4 Hz, CH₂), 6.65 (bs, 2H, NH₂), 7.39 (d, 1H, J=8.5 Hz,aromatic H), 7.47 (dd, 1H, J=11.0 Hz, J=1.8 Hz, aromatic H), 7.70 (d,2H, J=8.7 Hz, aromatic H), 7.86 (dd, 2H, J=9.2 Hz, J=1.8 Hz, aromaticH), 8.20 (d, 1H, J=1.8 Hz, aromatic H), 11.25 (s, 1H, CF₃CO₂H). ESI massspectrum z (rel. intensity) 436.8 (M+H, 100). HRMS (Q-TOF) calc.437.148590, obs. 437.149700.

Example 61 1-(3′-Aminobenzisoxazol-5′-yl)-5-[(2-(N-pyrrolidino)-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]tetrazole

The title compound was prepared in an analogous fashion as the TFA salt.¹H NMR (DMSO-d₆) δ 1.84 (m, 8H, CH₂), 3.17 (m, 4H, CH₂), 3.41 (m, 4H,CH₂), 6.95 (d, 1H, J=7.7 Hz, aromatic H), 7.02 (s, 1H, aromatic H), 7.46(t, 1H, J=8.4 Hz, aromatic H), 7.71 (d, 2H, J=8.7 Hz, aromatic H), 7.86(dd, 2H, J=8.8 Hz, J=1.8 Hz, aromatic H), 8.20 (d, 1H, J=2.2 Hz,aromatic H), 10.69 (s, 1H, CF₃CO₂H). ESI mass spectrum z (rel.intensity) 488.1 (M+H, 100).

Example 621-(1′-Amino-isoquinol-7′-yl)-5-[[(2′-aminosulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]tetrazole,trifluoroacetate salt Preparation of Ethyl1-(isoquinol-7′-yl)-5-tetrazole carboxylate

7-Aminoisoquinoline (4.81 g, 33.4 mmol) (J. Chem. Soc. 1951, 2851) wasdissolved in 100 mL of dichloromethane under a nitrogen atmosphere.Triethylamine (5.60 mL, 40.2 mmol, 1.2 eq.) was added to theisoquinoline solution. Ethyl oxalylchloride (4.10 mL, 36.7 mmol, 1.1eq.) was added dropwise over 30 minutes and the reaction was stirred for60 min. at ambient temperature. The solution was diluted with 100 mL ofdichloromethane, washed with water (2×50 mL) and brine (1×50 mL),filtered through phase separatory paper, and evaporated to give a paleyellow solid. This solid was dissolved in 50 mL of dichloromethane andhexanes (100 mL) was added. The resulting precipitate was isolated byfiltration and dried under vacuum to give[(isoquinol-7′-yl)amino]-oxoacetic acid, ethyl ester as an off-whitesolid (7.60 g, 93% yield). ¹H NMR (CDCl₃) δ 1.47 (t, 3H, J=7.1 Hz,OCH₂CH ₃), 4.47 (q, 2H, J=7.2 Hz, OCH₂CH₃), 7.63 (d, 1H, J=5.5 Hz,aromatic H), 7.78 (dd, 1H, J=8.9 Hz, J=2.0 Hz, aromatic H), 7.86 (d, 1H,J=8.8 Hz, aromatic H), 8.50 (d, 1H, J=1.9 Hz, aromatic H), 8.52 (d, 1H,J=5.8 Hz, aromatic H), 9.13 (bs, 1H, NH), 9.27 (s, 1H, aromatic H).C₁₃H₁₂N₂O₃ 244.25

A solution of triphenylphosphine (17.65 g, 67.3 mmol, 2 eq.) in 500 mLof carbon tetrachloride was stirred at 0° C. for 60 minutes.[(Isoquinol-7′-yl)amino]-oxoacetic acid, ethyl ester (8.15 g, 33.4 mmol)was added and heated at reflux for 16 hours. The solution was cooled toambient temperature and the precipitate was filtered off. The filtratewas evaporated to dryness and dissolved in 125 mL of acetonitrile.Sodium azide (2.17 g, 33.4 mmol) was added and the reaction mixture wasstirred for 16 hours at ambient temperature. The solvent was evaporatedand the resulting residue was dissolved in 200 mL of ethyl acetate. Theethyl acetate solution was washed with water (2×100 mL) and brine (1×50mL), dried over magnesium sulfate, and evaporated. The crude materialwas purified by silica gel flash chromatography eluting with 1:1 ethylacetate to hexane to give the title compound as an off-white solid (3.85g, 43% yield). ¹H NMR (CDCl₃) δ 1.23 (t, 3H, J=7.7 Hz, OCH₂CH₃), 4.39(q, 2H, J=7.1 Hz, OCH₂CH₃), 7.98 (d, 1H, J=5.5 Hz, aromatic H), 8.07(dd, 1H, J=8.8 Hz, J=2.2 Hz, aromatic H), 8.24 (d, 1H, J=8.7 Hz,aromatic H), 8.55 (d, 1H, J=1.4 Hz, aromatic H), 8.69 (d, 1H, J=5.5 Hz,aromatic H), 9.47 (s, 1H, aromatic H). C₁₃H₁₁N₅O₂ 269.26

Preparation of1-(1′-Amino-isoquinol-7′-yl)-5-[[(2′-aminosulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]tetrazole,trifluoroacetate salt

To a solution of(2′-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)amine (0.40 g,1.24 mmol) in 15 mL of anhydrous dichloromethane under nitrogen wasadded trimethyl aluminum (3.00 mL, 6.00 mmol, 2M in heptane). Thesolution was stirred for 15 minutes at ambient temperature. Ethyl1-(isoquinol-7′-yl)-5-tetrazole carboxylate (0.35 g, 1.30 mmol) in 15 mLof anhydrous dichloromethane was added slowly and the reaction mixturewas allowed to stir for 16 hours at ambient temperature. The reactionwas quenched with 5 mL 1N hydrochloric acid and diluted with 20 mLdichloromethane. The phases were separated and the dichloromethane phasewas washed with water (2×20 mL) and brine (1×20 mL), dried overmagnesium sulfate, and evaporated. The crude material was purified bysilica gel flash chromatography eluting with 0–30% ethyl acetate indichloromethane to give1-(isoquinol-7′-yl)-5-[(2′-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)carbonylamino]tetrazoleas a pale yellow solid (0.23 g, 33% yield). ¹H NMR (CDCl₃) δ 1.05 (s,9H, tert-butyl), 7.29 (d, 3H, J=1.6 Hz, aromatic H), 7.42 (dd, 1H,J=11.3 Hz, J=1.8 Hz, aromatic H), 7.52 (td, 1H, J=4.0 Hz, J=1.4 Hz,aromatic H), 7.56 (td, 1H, J=7.4 Hz, J=1.5 Hz, aromatic H), 7.81 (d, 1H,J=5.8 Hz, aromatic H), 7.89 (dd, 1H, J=8.8 Hz, J=2.2 Hz, aromatic H),8.07 (d, 1H, J=8.8 Hz, aromatic H), 8.16 (dd, 1H, J=7.7 Hz, J=1.5 Hz,aromatic H), 8.31 (bs, 1H, NH), 8.34 (t, 1H, J=8.0 Hz, aromatic H), 8.72(d, 1H, J=5.9 Hz, aromatic H), 9.42 (s, 1H, aromatic H), 9.47 (bs, 1H,NH). MS (ES+): 546.3 (M+H)⁺. C₂₇H₂₄FN₇O₃S 545.57

1-(Isoquinol-7′-yl)-5-[(2′-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)carbonylamino]tetrazole(0.12 g, 0.220 mmol) was dissolved in 50 mL of dichloromethane.meta-Chloroperbenzoic acid (.60%) (90.1 mg, 0.313 mmol, 1.4 eq) wasadded and the reaction mixture was refluxed for 4 hours. The solutionwas poured into 20 mL of saturated sodium bicarbonate. The phases wereseparated and the aqueous layer was extracted with dichloromethane (2×25mL). The combined organic solution was washed with water (2×20 mL) andbrine (1×25 mL), filtered through phase separatory paper, and evaporatedto give the N-oxide as an off-white solid. MS (ES+): 584.2 (M+Na)⁺. TheN-oxide was dissolved in 10 mL of anhydrous pyridine and tosyl chloride(63.3 mg, 0.332 mmol) was added. The reaction was stirred at ambienttemperature for 3 hours. The pyridine was removed under reduced pressureand to the residue was added 10 mL ethanolamine and the reaction mixturewas stirred at ambient temperature for 3 hours. The reaction mixture waspoured onto cracked ice and extracted with ethyl acetate (3×50 mL). Thecombined organic solution was washed with brine (1×50 mL), dried overmagnesium sulfate, and evaporated to give a yellow foam. This foam wasdissolved in 20 mL of dichloromethane and evaporated to give the1-aminoisoquinoline product as a pale yellow solid (0.07 g, 57% yield).¹H NMR (CDCl₃) δ 1.06 (s, 9H, tert-butyl), 4.01 (bs, 1H, NH), 5.42 (bs,2H, NH₂), 7.13 (d, 1H, J=5.8 Hz, aromatic H), 7.26 (m, 2H, aromatic H),7.38 (dd, 1H, J=11.4 Hz, J=1.8 Hz, aromatic H), 7.50 (td, 1H, J=7.3 Hz,J=1.5 Hz, aromatic H), 7.58 (td, 1H, J=7.3 Hz, J=1.5 Hz, aromatic H),7.78 (dd, 1H, J=8.7 Hz, J=2.2 Hz, aromatic H), 7.88 (d, 1H, J=8.8 Hz,aromatic H), 8.05 (d, 1H, J=5.9 Hz, aromatic H), 8.16 (d, 1H, J=8.1 Hz,aromatic H), 8.18 (s, 1H, aromatic H), 8.30 (t, 1H, J=8.2 Hz, aromaticH). MS (ES+) 561.2 (M+H)⁺. C₂₇H₂₅FN₈O₃S 560.59

The 1-aminoisoquinoline compound was dissolved in 5 mL oftrifluoroacetic acid and the reaction brought to reflux for 90 minutes.The solvent was removed and the residue was dissolved in acetonitrileand purified by HPLC (C18 reverse phase, eluting with acetonitrile andwater with 0.05% trifluoroacetic acid added). Evaporation of thesolvents gave the title compound as a white solid (45.4 mg, 59% yield).¹H NMR (DMSO-d₆) δ 7.22 (d, 1H, J=8.0 Hz, aromatic H), 7.34 (d, 3H,J=6.9 Hz, aromatic H), 7.44 (bs, 1H, NH), 7.62 (m, 4H, aromatic H), 7.82(d, 1H, J=7.0 Hz, aromatic H), 8.02 (d, 1H, J=6.6 Hz, aromatic H), 8.18(d, 1H, J=8.8 Hz, aromatic H), 8.28 (d, 1H, J=8.4 Hz, aromatic H), 8.96(bs, 1H, NH), 11.38 (bs, 1H, CF₃CO₂H). MS (APCI+) 505.3 (M+H)⁺. HRMS(ES+) for C₂₃H₁₇FN₈O₃S calc. (M+H)⁺ 505.1206; found 505.1221.

Example 631-(1′-Amino-isoquinol-7′-yl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]tetrazole,mesylate salt

The title compound was prepared in an analogous fashion as the mesylatesalt. ¹H NMR (DMSO-d₆) δ 2.30 (s, 3H, CH₃), 2.94 (s, 3H, CH₃), 7.26 (d,1H, J=9.9 Hz, aromatic H), 7.36 (d, 1H, J=8.7 Hz, aromatic H), 7.42 (d,2H, J=5.8 Hz, aromatic H), 7.65 (t, 1H, J=7.7 Hz, aromatic H), 7.72 (d,1H, J=7.7 Hz, aromatic H), 7.77 (d, 1H, J=5.9 Hz, aromatic H), 8.08 (d,1H, J=6.6 Hz, aromatic H), 8.20 (d, 1H, J=8.8 Hz, aromatic H), 8.32 (dd,1H, J=5.8 Hz, J=1.8 Hz, aromatic H), 8.98 (bs, 1H, NH), 11.42 (bs, 1H,CH₃SO₃ H). MS (APCI) 504.2 (M+H)⁺. HRMS (Q-TOF) for C₂₄H₁₈FN₇O₃S calc.(M+H)⁺ 504.125413; found 504.124200.

Example 641-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(2′aminosulfonylphenyl)pyrimidin-2-yl)aminocarbonyl]pyrazole

The pyrazole carboxylic acid obtained in example 11 was subjected to thestandard acid chloride coupling protocol withamino-2′-t-butylaminosulfonylphenyl-pyrimidin-2-yl to afford the coupledpyrimidyl amide precursor. This compound was then treated withacetoneoxime (NaH/DMF) followed by acid hydrolysis as per example 11 toafford the amino benzisoxazole derivative. Removal of the tert-butylgroup by treatment with TFA (1 mL) at 100° C. followed by purificationvia reverse phasew preparation HPLC (acetonitrile/water: 2% TFA) andlyophilization afforded the titled compound as colorless crystals. ESImass spectrum m/z (relative intensity) 545 (M+H, 100).

Example 651-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[4′(2″-methylimidazol-1″-yl)phenyl)aminocarbonyl]pyrazole,TFA salt

To a suspension of NaH (4.8 g, 120 mmol, prewashed with THF (3×5 mL) inTHF (100 mL) was added a solution of 1-fluoro-4-nitrobenzene (14.1 g,100 mmol) and 2-methylimidazole (8.2 g, 100 mmol) in THF (50 mL) at 0°C. The mixture was refluxed for 16 hours and cooled to room temperature.To it was added EtOAc (200 mL) and water (100 mL). The organic layer wasseparated, washed with water and brine, dried over MgSO₄, andconcentrated to give the crude nitro compound. A solution of the nitrointermediate in MeOH (200 mL) was treated with hydrogen gas in a balloonin the presence of 5% Pd on carbon (1.5 g) at room temperature for 24hours. The mixture was filtered and the filtrate was concentrated togive 4-(2′-methylimidazol-1′-yl)aniline (16.5 g, 95.4% for the twosteps) as a pale yellow solid. ¹H NMR (CDCl₃) δ 7.05 (dd, J=6.4 Hz,J=2.1 Hz, 2H), 6.98 (d, J=1.1 Hz, 1H), 6.93 (d, J=1.1 Hz, 1H), 6.73 (dd,J=6.4 Hz, J=2.1 Hz, 2H), 3.85 (bs, 2H), 2.31 (s, 3H); MS(CI) m/z 174(M+H, 100).

To a solution of1-(4′-fluoro-3′-cyanophenyl)-3-trifluoromethyl-5-pyrazolecarboxylic acid(2 g, 6.39 mmol) in CH₃CN (30 mL) was added SOCl₂ (5.1 g, 42.8 mmol) andthe resulting solution was refluxed for 2 hours. The mixture wasconcentrated on an evaporator and the residue was dissolved in MeOH (20mL). The resulting solution was refluxed for 30 minutes, and thenconcentrated and purified by silica gel chromatography with CH₂Cl₂ togive methyl1-(4′-fluoro-3′-cyanophenyl)-3-trifluoromethyl-5-pyrazolecarboxylicester (1.93 g, 92%). ¹H NMR (CDCl₃) δ 7.78 (dd, J=5.6 Hz, J=2.6 Hz, 1H),7.73 (dd, J=8.4 Hz, J=3.4 Hz, 1H), 7.36 (t, J=8.4 Hz, 1H), 7.30 (s, 1H),3.88 (s, 3H); ¹⁹F NMR (CDCl₃) δ −63.01, −104.60; MS(CI) m/z 331 (M+NH₄,100).

To a solution of acetone oxime (0.67 g, 9.2 mmol) in DMF (20 mL) wasadded potassium tert-butoxide (1.0 M in THF, 9.2 mL) and the mixture wasstirred at room temperature for 15 minutes. To it was added a solutionof methyl1-(4′-fluoro-3′-cyanophenyl)-3-trifluoromethyl-5-pyrazolecarboxylicester (1.92 g, 6.15 mmol) in DMF (20 mL) and the resulting mixture wasstirred at room temperature for 20 hours and quenched with water (10mL). The mixture was extracted with EtOAc (100 mL) and the EtOAc layerwas washed with brine (10 mL×5), dried over MgSO₄, concentrated, andpurified by silica gel chromatography eluted with 80% CH₂Cl₂ in hexaneto give methyl1-(4′-isopropylideneaminooxy-3′-cyanophenyl)-3-trifluoromethyl-5-pyrazolecarboxylicester (1.53 g, 68%) as a white solid. ¹H NMR (CDCl₃) δ 7.69 (d, J=9.1Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.60 (dd, J=9.1 Hz, J=2.5 Hz, 1H), 7.26(s, 1H), 3.85 (s, 3H), 2.19 (s, 3H), 2.08 (s, 3H); ¹⁹F NMR (CDCl₃) δ−62.88; MS(ES+) m/z 367 (M+H, 100).

To a solution of methyl1-(4′-isopropylideneaminooxy-3′-cyanophenyl)-3-trifluoromethyl-5-pyrazolecarboxylicester (1.53 g, 4.18 mmol) in MeOH (13 mL) and CH₂Cl₂ (6 mL) was added18% HCl (13 mL) and the mixture was refluxed for 3 hours and thenconcentrated to remove organic solvents. The resulting aqueous solutionwas neutralized with 2N NaOH to pH 7 and extracted with EtOAc. The EtOAclayer was washed with brine, dried over MgSO₄, and concentrated to givemethyl1-(3′-aminobenzisoxozol-5-yl)-3-trifluoromethyl-5-pyrazolecarboxylicester (1.32 g, 96%) as a white solid. ¹H NMR (CD₃OD) δ 7.89 (d, J=2.1Hz, 1H), 7.63 (dd, J=8.8 Hz, J=2.2 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.40(s, 1H), 3.79 (s, 3H); ¹⁹F NMR (CD₃OD) δ −64.36; MS(ES+) m/z 327 (M+H,100).

A solution of methyl1-(3′-aminobenzisoxozol-5-yl)-3-trifluoromethyl-5-pyrazolecarboxylicester (260 mg, 0.8 mmol) in THF (10 mL) was treated with 2N NaOH (10 mL)at room temperature for 16 hours. The mixture was acidified with conc.HCl to pH 3 and extracted with EtOAc. The EtOAc layer was dried overNa₂SO₄ and concentrated to give1-(3′-aminobenzisoxozol-5-yl)-3-trifluoromethyl-5-pyrazolecarboxylicacid (240 mg, 96%). ¹H NMR (CD₃OD) δ 7.90 (d, J=1.9 Hz, 1H), 7.62 (dd,J=8.8 Hz, J=2.4 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.35 (s, 1H); ¹⁹F NMR(CD₃OD) δ −64.32; MS(ES+) m/z 311 (M−H, 100).

To a solution of1-(3′-aminobenzisoxozol-5-yl)-3-trifluoromethyl-5-pyrazolecarboxylicacid (240 mg, 0.77 mmol) in DMF (5 mL) was added4-(2′-methylimidazol-1′-yl)aniline (133 mg, 0.77 mmol), DMAP (99.5 mg,0.79 mmol), and PyBrop (372 mg, 0.79 mmol). The resulting mixture wasstirred at 60° C. for 16 hours, and quenched with EtOAc (100 ml) andwater (20 mL). The EtOAc layer was washed with 1N HCl (10 mL), 1N NaOH(10 mL), water (10 mL), and brine (10 mL×3), dried over MgSO₄, andconcentrated. The residue was purified by HPLC (CH₃CN—H₂O-0.05% TFA) togive the title compound (281 mg, 63%) as a white solid. ¹H NMR (CD₃OD) δ7.97 (d, J=0.8 Hz, 1H), 7.89 (d, J=9.1 Hz, 2H), 7.65 (dd, J=9.1 Hz,J=2.2 Hz, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.58 (d, J=2.2 Hz, 1H), 7.52 (d,J=8.8 Hz, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 2.54 (s, 3H); ¹³CNMR (CD₃OD) δ 163.74, 160.46, 158.79, 146.51, 141.45, 140.03, 135.89,131.89, 129.10, 127.59, 124.51, 122.77, 122.39 (TFA-CF₃), 120.04,119.62, 118.22, 110.87, 108.24, 11.29; ¹⁹F NMR (CD₃OD) δ −64.21, −77.51(TFA); MS(ES+) m/z 468.2 (M+H, 100); HRMS: calcd. 468.1396; obs.468.1381. Anal. (C₂₂H₁₆N₇O₂F₃+1.33TFA+0.11HCl+1.4H₂O): C, H, N, F, Cl.

Example 661-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[4′(2″-methylimidazol-1″-yl)-2′-fluorophenyl)aminocarbonyl]pyrazole,TFA salt

To a solution of 4-bromo-2-fluoroaniline (19.2 g, 100 mmol) in THF (100mL) at 0° C. was slowly added LiN(TMS)₂ (1M in THF, 200 mL) over 30minutes. After the resulting solution was warmed to room temperature, asolution of di-tert-butyl dicarbonate (21.8 g, 100 mmol) in THF (50 mL)was slowly added, stirred for 15 minutes, and filtered through a pad ofsilica gel. The filtrate was concentrated and recrystalized from hexaneto give 4-bromo-2-fluoro-1-tert-butoxycarbonylaniline (27.7 g, 95%). ¹HNMR (CDCl₃) δ 8.00 (t, J=8.8 Hz, 1H), 7.25–7.20 (m, 2H), 6.66 (bs, 1H),1.52 (s, 9H); ¹⁹F NMR (CDCl₃) δ −130.42; MS(ES+) m/z 290/292 (M+H, 100).

To a solution of 4-bromo-2-fluoro-1-tert-butoxycarbonylaniline (2.9 g,10 mmol) in THF (20 mL) at −78° C. was slowly added n-BuLi (2.5 M, 10mL). After the solution was stirred at that temperature for 30 minutes,B(OMe)₃ (4.68 g, 45 mmol) was added and the resulting mixture was warmedto room temperature over 2 hours. The mixture was concentrated and theresidue was dissolved in EtOAc (150 mL) and water (50 mL), acidifiedwith 1N HCl to pH 4 and filtered through a pad of Celite. The organiclayer was separated, washed with water and brine, dried over Na₂SO₄,concentrated, and purified by silica gel chromatography eluted withgradient solvents (CH₂Cl₂ to EtOAc) to give3-fluoro-4-tert-butoxycarbonylamino-phenylboronic acid (1.45 g, 56.9%)as a white solid. ¹H NMR. (CD₃OD) δ 7. 80 (s, 1H), 7. 47 (d, J=8.4 Hz,1H), 7.40 (d, J=12.8 Hz, 1H), 1.52 (s, 9H); ¹⁹F NMR (CD₃OD) δ −132.66;MS(ES−) m/z 254 (M−H, 100).

To a solution of 3-fluoro-4-tert-butoxycarbonylamino-phenylboronic acid(1.1 g, 4.35 mmol) in THF (10 mL) was added 2-methylimidazole (0.36 g,4.33 mmol), pyridine (3.4 g, 43 mmol), Cu(OAc)₂ (0.79 g, 4.33 mmol), and4 Å molecular sieves. After being stirred at room temperature for 16hours, the resulting mixture was diluted with EtOAc (100 mL) andfiltered through a pad of silica gel. The filtrate was concentrated andtreated with 3M HCl in EtOAc (10 mL) at room temperature for 1 hour, andthen water (20 mL) was added. The aqueous layer was neutralized with 1NNaOH to pH 8 and extracted with EtOAc. The organic layer was dried overNa₂SO₄ and concentrated to give2-fluoro-4-(2′-methylimidazol-1′-yl)aniline (0.4 g, 48.5% for the twosteps). ¹H NMR (CD₃OD) δ 7.25 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 7.20 (d,J=1.4 Hz, 1H), 7.17 (dd, J=8.5 Hz, J=1.8 Hz, 1H), 7.09 (d, J=1.5 Hz,1H), 6.91 (t, J=8.8 Hz, 1H), 3.74 (s, 3H); ¹⁹F NMR (CD₃OD) δ −135.71;MS(ES+) m/z 192 (M+H, 100);

To a solution of1-(3′-aminobenzisoxozol-5-yl)-3-trifluoromethyl-5-pyrazolecarboxylicacid (130 mg, 0.42 mmol) in DMF (15 mL) was added2-fluoro-4-(2′-methylimidazol-1′-yl)aniline (80 mg, 0.42 mmol),diisopropylethylamine (0.2 mL), PyBrop (194 mg, 0.42 mmol), and 4 Åmolecular sieves. The resulting mixture was stirred at room temperaturefor 30 minutes and at 75° C. for 16 hours and EtOAc (100 ml) was added.The mixture was filtered through a pad of Celite, and the filtrate waswashed with 1N HCl (5 mL×2), 1N NaOH (5 mL×2), water (10 mL), and brine(5 mL×4), dried over MgSO₄, and concentrated. The residue was purifiedby silica gel TLC plates eluted with 10% MeOH in EtOAc, followed byfurther purification by HPLC (CH₃CN—H₂O-0.05% TFA) to give the titlecompound (75 mg, 37%) as a white solid. ¹H NMR (CD₃OD) δ 8.09 (t, J=8.4Hz, 1H), 7.97 (d, J=1.9 Hz, 1H), 7.66 (dd, J=8.8 Hz, J=2.2 Hz, 1H), 7.67(d, J=2.1 Hz, 1H), 7.58 (d, J=2.2 Hz, 1H), 7.55 (dd, J=9.1 Hz, J=2.1 Hz,1H), 7.50 (d, J=9.1 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 2.56(s, 3H); ¹³C NMR (CD₃OD) δ 163.76, 160.43, 159.05, 157.17, 154.67,146.80, 143.78, 139.61, 135.74, 129.10, 127.30, 124.48, 123.35, 121.03,120.08, 119.77, 118.23, 115.47, 115.23, 110.92, 108.65, 11.33; ¹⁹F NMR(CD₃OD) δ −64.21, −77.62 (TFA), −121.45; MS(ES+) m/z 486.2 (M+H, 100).Anal. (C₂₂H₁₅N₇O₂F₄+1.3TFA+1H₂O): C, H, N, F.

Example 671-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[4′(1″-methylimidazol-2″-yl)-2′-fluorophenyl)aminocarbonyl]pyrazole,TFA salt

To a solution of 1N-methylimidazole (1.64 g, 20 mmol) in THF 40 mL) at−78° C. was added nBuLi (2.5 M, 9.6 mL) and the resulting solution wasstirred at −78° C. for 30 minutes. After Bu₃SnCl (7.18 g, 22 mmol) wasadded, the resulting mixture was slowly warmed to room temperature over2 hours and was stirred for an additional 16 hours. To4-bromo-2-fluoro-1-tert-butoxycarbonylaniline (0.58 g, 2 mmol) andPd(PPh₃)₄ (92 mg, 0.08 mmol) was added the above solution (15 mL) andthe resulting mixture was degassed and filled with nitrogen three times.The mixture was refluxed under nitrogen for 18 hours, and was cooled toroom temperature. After saturated aqueous KF (10 mL) was added, theresulting mixture was stirred for 1 hour and filtered through a pad ofCelite. The filtrate was washed with water and brine, dried over MgSO₄,concentrated, and purified by silica del chromatography with EtOAc togive 2-fluoro-4-(1′-methylimidazol-2′-yl)-1-tert-butoxycarbonylaniline(0.35 g, 60%) as a white solid. ¹H NMR (CDCl₃) δ 8.19 (t, J=8.0 Hz, 1H),7.42 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 7.36 (d, J=9.1 Hz, 1H), 7.10 (d,J=1.1 Hz, 1H), 6.96 (s, 1H), 6.80 (bs, 1H), 3.75 (s, 3H), 1.54 (s, 9H);¹⁹F NMR (CDCl₃) δ −132.59; MS(ES+) m/z 292.2 (M+H, 100).

To a solution of2-fluoro-4-(1′-methylimidazol-2′-yl)-1-tert-butoxycarbonylaniline (0.33g, 1.13 mmol) in EtOAc (10 mL) was added 3M HCl (5 mL) and the resultingsolution was stirred at room temperature for 30 minutes. The solutionwas cooled to 0° C., neutralized with 50% NaOH to pH 8, and extractedwith EtOAc (50 mL×3). The EtOAc layer was concentrated and purified bysilica gel chromatography eluted with 5% MeOH in EtOAc to give2-fluoro-4-(1′-methylimidazol-2′-yl)aniline (0.18 g, 83%). ¹H NMR(CD₃OD) δ 7.54 (d, J=2.2 Hz, 1H), 7.51 (d, J=2.2 Hz, 1H), 7.37 (dd,J=11.8 Hz, J=2.2 Hz, 1H), 7.27 (dd, J=8.4 Hz, J=2.2 Hz, 1H), 6.97 (t,J=8.8 Hz, 1H), 3.88 (s, 3H) ¹⁹F NMR (CD₃OD) δ −136.77 (dd, J=90.1 Hz,J=9.1 Hz); MS(ES+) m/z 192 (M+H, 100).

To a solution of1-(3′-aminobenzisoxozole-5-yl)-3-trifluoromethyl-5-pyrazolecarboxylicacid (30 mg, 0.096 mmol) in DMF (2 mL) was added2-fluoro-4-(1′-methylimidazol-2′-yl)aniline (20.4 mg, 0.106 mmol),diisopropylethylamine (0.2 mL), and PyBrop (49.4 mg, 0.106 mmol). Theresulting mixture was stirred at 60° C. for 16 hours and quenched withEtOAc (75 ml) and water (5 mL). The EtOAc layer was washed with 1N HCl(5 mL), 1N NaOH (5 mL), and brine (5 mL×4), dried over MgSO₄, andconcentrated. The residue was purified on silica gel TLC plates with 10%MeOH in EtOAc, followed by further purification by HPLC (CH₃CN—H₂O-0.05%TFA) to give the title compound (19 mg, 40.8%) as a white solid. ¹H NMR(CD₃OD) δ 8.21 (t, J=8.1 Hz, 1H), 7.999 (dd, J=2.2 Hz, J=0.6 Hz, 1H),7.70–7.66 (m, 3H), 7.64 (d, J=2.2 Hz, 1H), 7.57 (dt, J=8.3 Hz, J=1.0 Hz,1H), 7.52 (dd, J=8.8 Hz, J=0.5 Hz, 1H), 7.48 (s, 1H), 3.93 (s, 3H); ¹³CNMR (CD₃OD) δ 163.78, 160.43, 159.02, 156.71, 154.22, 144.84, 143.78(CF₃), 139.64, 135.73, 129.09, 127.05, 126.51, 126.08, 120.52, 120.08,118.23, 117.99, 110.93, 108.71, 36.16; ¹⁹F NMR (CD₃OD) δ −64.21, −77.58(TFA), −123.46; MS(ES+) m/z 486.2 (M+H, 100).

Example 681-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[4′(2″-aminoimidazol-1″-yl)phenyl)aminocarbonyl]pyrazole,TFA salt

To a solution of 2-aminoimidazole sulfate (2.24 g, 17 mmol) in DMF (30mL) was added 4-bromo-1-nitrobenzene (3.4 g, 17 mmol), K₂CO₃ (4.69 g, 34mmol) and 18-crown-6 (50 mg), and the resulting mixture was stirred at80° C. for 16 hours. The mixture was cooled to room temperature, and wasdiluted with EtOAc (150 mL) and water (50 mL). The organic layer waswashed with brine (20 mL×5), dried over MgSO₄, and concentrated to give4-(2′-amino-imidazol-1′-yl)nitrobenzene (3.23 g, 98%). ¹H NMR (CD₃OD) δ8.38 (d, J=9.1 Hz, 2H), 7.73 (d, J=9.1 Hz, 2H), 6.90 (d, J=1.9 Hz, 1H),6.66 (d, J=1.9 Hz, 1H); MS(ES+) m/z 205 (M+H, 100).

A solution of 4-(2′-amino-imidazol-1′-yl)nitrobenzene (0.5 g, 2.45 mmol)in methanol (15 mL) was treated with hydrogen in a balloon in thepresence of 5% Pd on carbon (70 mg) at room temperature for 16 hours andthen filtered. The filtrate was concentrated to give4-(2′-amino-imidazol-1′-yl)aniline (0.35 g, 82%). ¹H NMR (CD₃OD) δ 7.08(dd, J=6.6 Hz, J=2.2 Hz, 2H), 6.77 (dd, J=6.6 Hz, J=2.2 Hz, 2H), 6.64(d, J=1.8 Hz, 1H), 6.58 (d, J=1.8 Hz, 1H); MS(ES+) m/z 175 (M+H, 100).

To a solution of1-(3′-aminobenzisoxozol-5-yl)-3-trifluoromethyl-5-pyrazolecarboxylicacid (110 mg, 0.35 mmol) in DMF (5 mL) was added freshly prepared4-(2′-amino-imidazol-1′-yl)aniline (110 mg, 0.63 mmol), iPrNEt₂ (1 mL),PyBrop (260 mg, 0.56 mmol), and 4 Å molecular sieves. The resultingmixture was stirred at room temperature for 16 hours and quenched withEtOAc (100 mL). The mixture was filtered and the filtrate was washedwith brine (5 mL×5) and 1N HCl ((10 mL×3). The combined HCl layers wereneutralized with 50% NaOH to pH 14 and extracted with EtOAc. The EtOAclayer was dried over Na₂SO₄, concentrated, and purified by HPLC(CH₃CN—H₂O−0.05% TFA) to give the title compound (81 mg, 50%) as a whitesolid. ¹H NMR (CD₃OD) δ 7.77 (d, J=1.5 Hz, 1H), 7.49 (dd, J=8.8 Hz,J=2.2 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.18 (s, 1H), 7.16 (dd, J=6.6 Hz,J=2.2 Hz, 2H), 7.12 (d, J=2.5 Hz, 1H), 7.07 (d, J=2.5 Hz, 1H), 6.96 (dd,J=6.6 Hz, J=2.2 Hz, 2H); ¹⁹F NMR (CD₃OD) δ −64.23, −77.76 (TFA); MS(ES+)m/z 469 (M+H, 100).

Example 691-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[4′(2″-N,N-dimethylaminomethylphenyl)-2′-fluorophenyl)aminocarbonyl]pyrazole,TFA salt

To a solution of 2-formylphenylboronic acid (5 g, 33.3 mmol) in THF (80mL) was added 4-bromo-2-fluoroaniline (4.2 g, 22.2 mmol) and Na₂CO₃ (2M,80 mL) and then was bubbled with nitrogen for 10 minutes. AfterPd(PPh₃)₄ (1.54 g, 1.33 mmol) was added, the resulting mixture wasrefluxed under nitrogen for 4 hours. The THF layer was separated,filtered through a pad of silica gel, and washed with THF to give 80 mLsolution of 4(2′-formylphenyl)-2-fluoroaniline in THF. MS(CI) m/z 233(M+NH₄, 100%). To the filtrate (15 mL from total 80 mL) was addedMe₂NH.HCl (0.68 g, 8.33 mmol) and the resulting mixture was refluxed for2 hours. The mixture was cooled to room temperature, and to it was addedMeOH (5 mL) and then NaBH₄ (0.32 g, 8.33 mmoL). After being stirred at50° C. for 1 hour, the mixture was cooled to room temperature again andquenched with 1N HCl to pH 1. The aqueous layer was separated,neutralized with 50% NaOH to pH 12, and extracted with EtOAc. The EtOAclayer was dried over MgSO₄, concentrated, and purified by silica gelchromatography eluted with EtOAc to give4-(2′-N,N-dimethylaminomethylphenyl)-2-fluoroaniline (0.89 g, 87.5%). ¹HNMR (CDCl₃) δ 7.49 (dd, J=8.8 Hz, J=1.8 Hz, 1H), 7.31–7.21 (m, 3H), 7.14(dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.97 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 6.80(t, J=8.8 Hz, 1H), 3.76 (bs, 2H), 3.34 (s, 2H), 2.17 (s, 6H); ¹⁹F NMR(CDCl₃) δ −136.19; MS(ES+) m/z 245.2 (M+H, 100).

To a solution of1-(4′-fluoro-3′-cyanophenyl)-3-trifluoromethyl-5-pyrazolecarboxylic acid(0.299 g, 1 mmol) in CH₃CN (20 mL) was added SOCl₂ (0.74 g, 6 mmol). Theresulting mixture was refluxed for 2 hours and then concentrated. To asolution of the residue in THF (25 mL) was added4-(2′-N,N-dimethylaminomethylphenyl)-2-fluoroaniline (0.29 g, 1.19 mmol)and N,N-diisopropylethylamine (1 mL). The resulting solution was stirredat room temperature for 16 hours and quenched with EtOAc (100 mL) and 1NHCl (50 mL). The organic layer was separated and washed with 1N NaOH (20mL) and brine, dried over MgSO₄, concentrated, and purified on silicagel TLC plates eluted with 10% MeOH in CH₂Cl₂ to give1-(4′-fluoro-3′-cyanophenyl)-3-trifluoromethyl-5-[4′(2″-N,N-dimethylaminomethylphenyl)-2′-fluorophenyl)aminocarbonyl]pyrazole(0.31 g, 59%). ¹H NMR (CDCl₃) δ 8.18 (t, J=8.4 Hz, 1H), 8.06 (bs, 1H),7.87–7.79 (m, 2H), 7.50 (dd, J=8.8 Hz, J=1.5 Hz, 1H), 7.42–7.30 (m, 5H),7.24 (d, J=7.0 Hz, 1H), 7.19 (s, 1H), 3.33 (s, 2H), 2.19 (s, 6H); ¹⁹FNMR (CDCl₃) δ −62.85, −104.83, −135.2; MS(ES+) m/z 526.3 (M+H, 100).

To a solution of acetone oxime (0.129 g, 1.77 mmol) in DMF (5 mL) wasadded potassium tert-butoxide (1.0 M in THF, 1.77 mL), and the mixturewas stirred at room temperature for 15 minutes. To it was then added asolution of1-(4′-fluoro-3′-cyanophenyl)-3-trifluoromethyl-5-[4′(2″-N,N-dimethylaminomethylphenyl)-2′-fluorophenyl)aminocarbonyl]pyrazole(0.31 g, 0.59 mmol) in DMF (5 mL), and the resulting mixture was stirredat room temperature for 20 hours and quenched with water (10 mL). Themixture was extracted with EtOAc (100 mL), and the EtOAc layer waswashed with brine (10 mL×5), dried over MgSO₄, and concentrated to givea residue. The residue was treated with 4M HCl in dioxane (10 mL) underreflux for 2 hours and concentrated. The resulting residue was dissolvedin EtOAc and water, and the EtOAc layer was dried over Na₂SO₄,concentrated, and purified on silica gel TLC plates eluted with 5% MeOHin CH₂Cl₂, followed by purification by HPLC (CH₃CN—H₂O-0.05% TFA) togive the title compound (37 mg, 11% for the two steps) as a white solid.¹H NMR (CD₃OD) δ 7.99 (dd, J=2.2 Hz, J=0.5 Hz, 1H), 7.83 (t, J=8.1 Hz,1H), 7.68 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 7.63–7.61 (m, 1H), 7.57–7.54 (m,1H), 7.52 (dd, J=8.8 Hz, J=0.6 Hz, 1H), 7.45 (s, 1H), 7.42–7.40 (m, 1H),7.24 (dd, J=11.2 Hz, J=1.9 Hz, 1H), 7.15 (dd, J=8.2 Hz, J=1.2 Hz, 1H),4.71 (s, 2H), 2.63 (s, 6H); ¹³C NMR (CD₃OD) δ 162.33, 159.00, 142.07,138.89, 138.40, 134.41, 130.78, 130.47, 129.96, 128.80, 127.76, 127.32,125.99, 125.40, 124.24, 124.11, 118.73, 116.92, 116.80, 116.71, 109.43,106.93, 57.68, 41.77; ¹⁹F NMR (CD₃OD) δ −64.20, −77.57 (TFA), −123.93;MS(ES+) m/z 539.2 (M+H, 100).

Example 70 Ethyl1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylatePreparation of ethyl 4-(2-furyl)-2,4-dioxobutyrate

To a suspension of sodium hydride (5.4 g of 60% dispersion in mineraloil, 136 mmol, mineral oil was removed by washing twice with hexanes) in100 mL of tetrahydrofuran at ambient temperature was added diethyloxalate (12.3 mL, 91 mmol). To this mixture was added 2-acetylfuran (5.0g, 45 mmol) as a solution in 25 mL of tetrahydrofuran. The resultingmixture was stirred at 70° C. for 1 h. The reaction was cooled to roomtemperature and then 10% HCl was added slowly until the solution wasacidic. The tetrahydrofuran was removed in vacuo and the residue wastaken up in ethyl acetate. The organics were washed with brine, dried(MgSO₄) and concentrated to afford 5.5 g (58%) of the title compoundwhich was used without purification.

Preparation of ethyl1-(3-cyano-4-fluorophenyl)-5-(2-furyl)pyrazole-3-carboxylate

To ethyl 4-(2-furyl)-2,4-dioxobutyrate (3.5 g, 16.7 mmol) in 50 mL ofglacial acetic acid was added 4-fluoro-3-cyanophenylhydrazine tinchloride (6.3 g, 16.7 mmol). The reaction was stirred at 100° C. for 4h. The reaction was allowed to cool to room temperature and the aceticacid was removed in vacuo. The residue was diluted with ethyl acetateand the organics were washed with saturated aq NaHCO₃ and brine, dried(MgSO₄) and concentrated. The residue was purified by recrystallizationfrom hexane/ethyl acetate to afford 2.5 g (46%) of the title compound.LRMS (ES+): 326.1 (M+H)⁺.

Preparation of ethyl1-(3-cyano-4-fluorophenyl)-pyrazole-3-carboxylate-5-carboxylic acid

To a solution of ethyl1-(3-cyano-4-fluorophenyl)-5-(2-furyl)pyrazole-3-carboxylate (1.30 g,4.0 mmol) in 8:8:12 carbon tetrachloride/acetonitrile/water was addedsodium periodate (3.85 g, 18 mmol) and ruthenium (III) chloridemonohydrate (20 mg, 0.09 mmol). The resulting biphasic reaction wasstirred vigorously at ambient temperature for 24 h. The reaction wasquenched with 10% aq HCl and diluted with ethyl acetate. The organicswere washed with brine, dried (MgSO₄), filtered through a pad of Celiteand concentrated. The residue was dissolved in 1:1 hexanes/ethyl acetateand extracted with sat'd aq Na₂CO₃ (2 times). The combined aqueousextracts were acidified and extracted with ethyl acetate. The ethylacetate extracts were washed with brine, dried (MgSO₄) and concentratedto afford 0.70 g (58%) of the title compound as a solid. LRMS (AP+):304.1 (M+H)⁺.

Preparation of ethyl1-(3-cyano-4-fluorophenyl)-5-[(2′-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate

To a solution of ethyl1-(3-cyano-4-fluorophenyl)-pyrazole-3-carboxylate-5-carboxylic acid(0.44 g, 1.45 mmol) in 10 mL of methylene chloride was added oxalylchloride (0.19 mL, 2.18 mmol) and 2 drops of dimethylformamide. Thereaction was stirred at ambient temperature for 6 h and then thevolatiles were removed in vacuo. The residue was dissolved in 10 mL ofmethylene chloride and then there was added 4-dimethylaminopyridine(0.53 g, 4.35 mmol). The reaction was stirred for 10 min and then therewas added (2′-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminehydrochloride (0.47 g, 1.45 mmol). The resulting mixture was allowed tostir at ambient temperature for 16 h. The reaction was diluted withethyl acetate and the organics were washed with 10% aq HCl, sat'd aqNaHCO₃ and brine, dried (MgSO₄), filtered through a pad of silica geland concentrated to afford 0.35 g (40%) of the title compound as asolid. LRMS (ES−): 606.1 (M−H)⁻.

Preparation of ethyl1-(4-isopropylideneaminooxy-3-cyanophenyl)-5-[(2′-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate

To a solution of acetone oxime (40 mg, 0.52 mmol) in 2 mL of DMF atambient temperature was added potassium tert-butoxide (1.2 mL of a 1.0 Msolution in tetrahydrofuran, 1.2 mmol). The reaction was stirred for 15min and then ethyl1-(3-cyano-4-fluorophenyl)-5-[(2′-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate(243 mg, 0.40 mmol) was added as a solution in 3 mL of DMF. Theresulting mixture was allowed to stir at ambient temperature for 18 h.The reaction was partitioned between ethyl acetate and sat'd aq ammoniumchloride and the organics were washed with brine, dried (MgSO₄), andconcentrated. The residue was purified by flash chromatography (elutionwith 2:1 hexanes/ethyl acetate) to afford 0.15 g (57%) of the titlecompound. LRMS (AP−): 658.9 (M−H)⁻.

Preparation of ethyl1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate

To a solution of ethyl1-(4-isopropylideneaminooxy-3-cyanophenyl)-5-[(2′-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate(0.14 g, 0.21 mmol) in 5 mL of absolute ethanol was added 4 mL of 6NHCl. The reaction was stirred at 80° C. for 1 h and then was cooled toroom temperature. The reaction was diluted with ethyl acetate and theorganics were washed with water and brine, dried (MgSO₄) andconcentrated. The residue was dissolved in 5 mL of trifluoroacetic acidand stirred at 80° C. for 30 min. The reaction was cooled andconcentrated and the residue was purified by prep HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andlyophilized to afford 34 mg (29%) of the compound of Example 70 as awhite powder. LRMS (AP+): 565.2 (M+H)⁺.

Example 711-(3′-Aminobenzisoxazol-5′-yl)-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylicacid

To a solution of ethyl1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate(0.20 g, 0.32 mmol) in 10 mL of 1:1 methanol/water was added potassiumhydroxide (20 mg, 0.35 mmol). The reaction was stirred at 60° C. for 2 hand then was cooled to room temperature and acidified with 10% aq HCl.The mixture was diluted with ethyl acetate, washed with brine, dried(MgSO₄) and concentrated. A portion of the residue (25 mg) was dissolvedin 5 mL of trifluoroacetic acid and stirred at 80° C. for 30 min. Thereaction was cooled and concentrated and the residue was purified byprep HPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradientwith 0.5% TFA) and lyophilized to afford 10 mg (40%) of the compound ofExample 71 as a white powder. LRMS (ES+): 537.2 (M+H)⁺.

Example 721-(3′-Aminobenzisoxazol-5′-yl)-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxamide

To a solution of1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylicacid (0.15 g, 0.25 mmol) in 50 mL of acetonitrile at 0° C. was addedtriethylamine (0.05 mL, mmol) and iso-butyl chloroformate (0.03 mL,mmol). This mixture was stirred for 30 min and then there was addedmethanolic ammonia (0.50 mL of a 2.0 M solution of ammonia in methanol,mmol). The reaction was allowed to stir with warming to room temperaturefor 18 h. The volatiles were removed in vacuo and the residue wasdiluted with ethyl acetate. The organics were washed with sat'd aqNaHCO₃ and brine, dried (MgSO₄) and concentrated. A portion of theresidue (25 mg) was dissolved in 5 mL of trifluoroacetic acid andstirred at 80° C. for 30 min. The reaction was cooled and concentratedand the residue was purified by prep HPLC (C18 reverse phase column,elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized toafford 12 mg (50%) of the compound of Example 72 as a white powder. LRMS(ES+): 536.2 (M+H)⁺.

Example 73 Ethyl1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylatePreparation of ethyl1-(3-cyano-4-fluorophenyl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate

To a solution of ethyl1-(3-cyano-4-fluorophenyl)-pyrazole-3-carboxylate-5-carboxylic acid(4.55 g, 15 mmol) in 100 mL of methylene chloride was added oxalylchloride (2.0 mL, 22.5 mmol) and 2 drops of dimethylformamide. Thereaction was stirred at ambient temperature for 6 h and then thevolatiles were removed in vacuo. The residue was dissolved in 100 mL ofmethylene chloride and then there was added 4-dimethylaminopyridine (5.5g, 45 mmol). The reaction was stirred for 10 min and then there wasadded 2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)amine hydrochloride(4.52 g, 15 mmol). The resulting mixture was allowed to stir at ambienttemperature for 16 h. The reaction was diluted with ethyl acetate andthe organics were washed with 10% aq HCl, sat'd aq NaHCO₃ and brine,dried (MgSO₄) and concentrated. The residue was purified by flashchromatography (elution with 3:1 hexane/ethyl acetate) to afford 1.55 g(18%) of the title compound as a solid. LRMS (AP+): 551.2 (M+H)⁺.

Preparation of ethyl1-(4-isopropylideneaminooxy-3-cyanophenyl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate

To a solution of acetone oxime (0.26 g, 3.6 mmol) in 20 mL of DMF atambient temperature was added potassium tert-butoxide (8.3 mL of a 1.0 Msolution in tetrahydrofuran, 8.3 mmol). The reaction was stirred for 15min and then ethyl1-(3-cyano-4-fluorophenyl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate(1.53 g, 2.77 mmol) was added as a solution in 10 mL of DMF. Theresulting mixture was allowed to stir at ambient temperature for 18 h.The reaction was partitioned between ethyl acetate and sat'd aq ammoniumchloride and the organics were washed with brine, dried (MgSO₄), andconcentrated. The residue was purified by flash chromatography (elutionwith 2:1 hexanes/ethyl acetate) to afford 1.28 g (77%) of the titlecompound. LRMS (ES−): 602.2 (M−H)⁻.

Preparation of ethyl1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate

To a solution of ethyl1-(4-isopropylideneaminooxy-3-cyanophenyl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate(1.3 g, 2.1 mmol) in 40 mL of absolute ethanol was added 40 mL of 6NHCl. The reaction was stirred at 80° C. for 1 h and then was cooled toroom temperature. The reaction was diluted with ethyl acetate and theorganics were washed with water and brine, dried (MgSO₄) andconcentrated. A portion (100 mg) of the residue was purified by prepHPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradient with0.5% TFA) and lyophilized to afford 30 mg of the compound of Example 73as a white powder. LRMS (ES+): 564.2 (M+H)⁺.

Example 741-(3′-Aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylicacid

To a solution of ethyl1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate(0.43 g, 0.76 mmol) in 20 mL of 1:1 methanol/water was added potassiumhydroxide (50 mg, 0.84 mmol). The reaction was stirred at 60° C. for 2 hand then was cooled to room temperature and acidified with 10% aq HCl.The mixture was diluted with ethyl acetate, washed with brine, dried(MgSO₄) and concentrated. A 25 mg portion of the residue was purified byprep HPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradientwith 0.5% TFA) and lyophilized to afford 10 mg of the compound ofExample 74 as a white powder. LRMS (ES−): 534.1 (M−H)⁻.

Example 751-(3′-Aminobenzisoxazol-5′-yl)-3-(hydroxymethyl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

To a solution of1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylicacid (0.41 g, 0.77 mmol) in tetrahydrofuran at −20° C. was addedtriethylamine (0.12 mL, 0.84 mmol) and iso-butyl chloroformate (0.11 mL,0.84 mmol). This mixture was stirred for 30 min and then there was addedsodium borohydride (60 mg, 1.54 mmol) in a minimal amount of water. Thereaction mixture was stirred with slow warming to room temperature for 1h and then was quenched with 10% aq HCl. After diluting with ethylacetate, the organics were washed with brine, dried (MgSO₄) andconcentrated in vacuo to afford 0.29 g of the title compound. A portion(25 mg) of the residue was purified by prep HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilizedto afford 10 mg of the compound of Example 75 as a white powder. MS(AP+): 522.2 (M+H)⁺.

Example 761-(3′-Aminobenzisoxazol-5′-yl)-3-[dimethylaminomethyl]-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole,trifluoroacetic acid salt

To a solution of1-(3′-aminobenzisoxazol-5′-yl)-3-hydroxymethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole(0.10 g, 0.19 mmol) in 25 mL of acetonitrile was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one (Dess-Martinperiodinane) (0.19 g, 0.44 mmol) in 10 mL of acetonitrile and 2 drops ofacetic acid. The resulting mixture was stirred at ambient temperaturefor 1 h. The reaction was poured into sat'd aq NaHCO₃ and extracted withmethylene chloride. The organics were washed with water and brine, dried(MgSO₄) and concentrated in vacuo. The residue was dissolved in 10 mL ofmethanol and then there was added dimethylamine hydrochloride (0.07 g,0.9 mmol) and sodium cyanoborohydride (0.011 g, 0.18 mmol). Theresulting mixture was allowed to stir at ambient temperature for 18 h.The methanol was removed in vacuo and the residue was quenched with 5 mLof 10% aq HCl. The mixture was extracted with ether to remove unreactedstarting materials. The aqueous layer was then made basic and extractedwith ethyl acetate. The ethyl acetate layer was washed with brine, dried(MgSO₄) and concentrated in vacuo. The residue was purified by prep HPLC(C18 reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5%TFA) and lyophilized to afford 10 mg (8%) of the compound of Example 76as a white powder. MS (ES+): 549.2 (M+H)⁺.

Example 77 Ethyl1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylatePreparation of ethyl1-(3-cyano-4-fluorophenyl)-5-(2-furyl)pyrazole-4-carboxylate

To a solution of ethyl 3-(2-furyl)-3-ketopropionate (2.1 g, 11.5 mmol)in 20 mL of benzene was added dimethylformamide dimethylacetal (2.3 mL,17.3 mmol). The resulting solution was stirred at 80° C. for 2 h. Thereaction was cooled, filtered through a pad of silica gel andconcentrated in vacuo. A portion of the residue (0.60 g, 2.54 mmol) wasdissolved in 20 mL of glacial acetic acid and then there was added4-fluoro-3-cyanophenylhydrazine tin chloride (1.05 g, 2.8 mmol). Thereaction mixture was stirred at 100° C. for 4 h. The reaction wasallowed to cool to room temperature and the acetic acid was removed invacuo. The residue was diluted with ethyl acetate and the organics werewashed with saturated aq NaHCO₃ and brine, dried (MgSO₄) andconcentrated. The residue was purified by flash chromatography (elutionwith gradient of 6:1−>3:1 hexanes/ethyl acetate) to afford 0.32 g (39%)of the title compound. LRMS (ES+): 326.2 (M+H)⁺.

Preparation of ethyl1-(3-cyano-4-fluorophenyl)-pyrazole-4-carboxylate-5-carboxylic acid

To a solution of ethyl1-(3-cyano-4-fluorophenyl)-5-(2-furyl)pyrazole-4-carboxylate (0.3 g,0.92 mmol) in 6:6:9 carbon tetrachloride/acetonitrile/water was addedsodium periodate (0.89 g, 4.15 mmol) and ruthenium (III) chloridemonohydrate (20 mg, 0.09 mmol). The resulting biphasic reaction wasstirred vigorously at ambient temperature for 6 h. An additional portionof sodium periodate was added (0.45 g, 2.08 mmol) and the reaction wasallowed to stir an additional 16 h. The reaction was quenched with 10%aq HCl and diluted with ethyl acetate. The organics were washed withbrine, dried (MgSO₄), filtered through a pad of Celite and concentratedto afford 0.28 g (100%) of the title compound as a solid, which wassufficiently pure to be used without purification. LRMS (ES−): 302.0(M−H)⁻.

Preparation of ethyl1-(3-cyano-4-fluorophenyl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-5-carboxylate

To a solution of ethyl1-(3-cyano-4-fluorophenyl)-pyrazole-4-carboxylate-5-carboxylic acid(0.28 g, 0.92 mmol) in 10 mL of methylene chloride was added oxalylchloride (0.19 mL, 2.18 mmol) and 2 drops of dimethylformamide. Thereaction was stirred at ambient temperature for 6 h and then thevolatiles were removed in vacuo. The residue was dissolved in 10 mL ofmethylene chloride and then there was added 4-dimethylaminopyridine(0.34 g, 2.76 mmol). The reaction was stirred for 10 min and then therewas added (2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminehydrochloride (0.28 g, 0.92 mmol). The resulting mixture was allowed tostir at ambient temperature for 16 h. The reaction was diluted withethyl acetate and the organics were washed with 10% aq HCl, sat'd aqNaHCO₃ and brine, dried (MgSO₄), filtered through a pad of silica geland concentrated to afford 0.4 g (80%) of the title compound as a solid.LRMS (ES+): 573.1 (M+Na)⁺.

Preparation of ethyl1-(4-isopropylideneaminooxy-3-cyanophenyl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate

To a solution of acetone oxime (70 mg, 0.94 mmol) in 5 mL of DMF atambient temperature was added potassium tert-butoxide (1.1 mL of a 1.0 Msolution in tetrahydrofuran, 1.1 mmol). The reaction was stirred for 15min and then ethyl1-(3-cyano-4-fluorophenyl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate(200 mg, 0.36 mmol) was added as a solution in 4 mL of DMF. Theresulting mixture was allowed to stir at ambient temperature for 18 h.The reaction was partitioned between ethyl acetate and sat'd aq ammoniumchloride and the organics were washed with brine, dried (MgSO₄),filtered through a pad of silica gel and concentrated to afford 0.14 g(65%) of the title compound, which was sufficiently pure to be usedwithout purification. LRMS (ES+): 626.2 (M+Na)⁺.

Preparation of ethyl1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate

To a solution of ethyl1-(4-isopropylideneaminooxy-3-cyanophenyl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate(0.14 g, 0.21 mmol) in 5 mL of absolute ethanol was added 4 mL of 6NHCl. The reaction was stirred at 80° C. for 1 h and then was cooled toroom temperature. The reaction was diluted with ethyl acetate and theorganics were washed with water and brine, dried (MgSO₄) andconcentrated. The residue was purified by prep HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilizedto afford 40 mg (30%) of the compound of Example 77 as a white powder.LRMS (AP+): 564.3 (M+H)⁺.

Example 781-(3′-Aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylicacid

To a solution of ethyl1-(3′-aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate(30 mg, 0.053 mmol) in 10 mL of 1:1 methanol/water was added potassiumhydroxide (20 mg, 0.36 mmol). The reaction was stirred at 60° C. for 1 hand then was cooled to room temperature and concentrated. The residuewas purified by prep HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford 18 mg (64%)of the compound of Example 78 as a white powder. LRMS (ES−): 534.1(M−H)⁻.

Example 791-(1′,2′,3′,4′-tetrahydroisoquinol-7′-yl)-3-methyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazolemesylate

The title compound is prepared in an analogous fashion. MS (ES+) 488.0(M+H)⁺ (100%).

Example 801-(1′-Amino-isoquinol-7′-yl)-3-[(2′-methylaminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]-5-methyl-pyrazolemesylate

The title compound is prepared in an analogous fashion. MS (ES+) 513.0(M+H)⁺ (100%).

Example 811-(4′-amino-isoquinol-7′-yl)-3-methyl-5-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazolemesylate

The title compound is prepared in an analogous fashion. MS (ES+) 498.0(M+H)⁺ (100%).

Example 821-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate Preparation of1-(isoquinol-7-yl)-3-trifluoromethyl-5-pyrazole-craboxylic acid

An acetic acid (500 mL) solution of the 7-hydrazino-isoquinoline-tinsalt (50.93 g (146 mmol) (prepared as discussed in Example 1) and4,4,4-trifluoromethyl-1-(2-furyl)-1,3-butanedione (20.1 g, 97.57 mmoL)were gently refluxed overnight. The reaction was cooled and concentratedto a small volume. The mixture was quenched with sat. sodium bicarbonate(100 mL) and the organics were extracted with ethyl acetate (4×100 mL),dried (MgSO₄), and evaporated to a brown oil. Chromatography on silicagel (hexane:ethylacetate 1:1) afforded the desired pyrazole compound (40g). ¹HNMR (CDCl₃) δ: 8.33 (s, 1H), 8.15 (d, 2H), 7.87 (dd, 1H), 7.51 (s,1H), 7.08 (s, 4H), 6.44 (m, 1H), 6.32 (d, 1H) ppm. ESI (+ve) massspectrum analysis m/z (relative intensity) 330 (M+H, 100).

The product from above (40 g, 121 mmol) was dissolved in acetone (1 L).The solution was gently heated to 60° C., followed by the addition ofKMnO₄ (141 g, 890 mmoL) portionwise while maintaining the internaltemperature of the reaction to 60° C. Care should be taken to preventthe reaction from taking off. The reaction was judged to be completed byTLC within 10 min. The solution was cooled and gradually quenched with asaturated sodium bisulfite solution (1 L). The clear solution wasextracted with ethyl acetate (3×200 mL) to remove by-products. Theaqueous layer was carefully adjusted to pH 4 whereby the desiredcompound precipitated out and was filtered and dried over nitrogen (35 gobtained). ¹HNMR (DMSO d₆)δ: 9.50 (bs, 1H), 8.64 (bs, 1H), 8.44 (s, 1H),8.14 (m, 1H), 8.00 (m, 2H), 7.60 (s, 1H) ppm. ESI (−ve) mass spectrumanalysis m/z (relative intensity) 306 (M−H, 100).

Preparation of1-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate

The product is prepared in an analogous fashion as Example 1. MS (ES+)551.8 (M+H)⁺ (100%); mp 173° C.

Example 831-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(2-fluoro-4-(N-pyrrolidinocarbonyl)-phenyl)carbonylamino]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. MS (ES+) 512.9(M+H)⁺ (100%); mp 225° C.

Example 841-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. MS (ES+) 570.1(M+H)⁺ (100%).

Example 851-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. MS (ES+) 553.1(M+H)⁺ (100%).

Example 861-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(2′-aminosulfonyl-3-fluoro-[1,1′-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. MS (ES+) 571.1(M+H)⁺ (100%); mp 248–250° C.

Example 871-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(5-(2′-methylsulfonylphenyl)pyrid-2-yl)carbonylamino]pyrazolebistrifluoroacetate

The title compound is prepared in an analogous fashion. MS (ES+) 553.1(M+H)⁺ (100%).

Example 881-(1′-Amino-isoquinol-7′-yl)-3-methyl-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. MS (ES+) 517.3(M+H)⁺ (100%); mp 175–177° C.

Example 891-(1′-Amino-isoquinol-7′-yl)-3-methyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. MS (AP+) 516.2(M+H)⁺ (100%); mp 203° C.

Example 901-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(2′-aminosulfonyl-3-chloro-[1,1′]-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. MS (ES+) 587.1(M+H)⁺ (100%); mp 194° C.

Example 911-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(2′-aminosulfonyl-3-methyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. MS (ES+) 567.3(M+H)⁺ (100%).

Example 921-(1′-Amino-isoquinol-7′-yl)-3-trifluoromethyl-5-[(2′-methylaminosulfonyl-[1,1′]-biphen-4-yl)carbonylamino]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. MS (ES+) 567.2(M+H)⁺ (100%); mp 166° C.

Example 931-(1′-Aminoisoquinol-7′-yl)-3-ethyl-5-[(2′-methylaminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 527 (M+H, 100).mp 173° C.

Example 941-(1′-Aminoisoquinol-7′-yl)-3-ethyl-5-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazolemesylate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 512 (M+H, 100).mp 185° C.

Example 951-(1′-Aminoisoquinol-7′-yl)-3-propyl-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 527 (M+H, 100).

Example 961-(1′-Aminoisoquinol-7′-yl)-3-propyl-5-[(2′-methylaminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 541 (M+H, 100).

Example 971-(1′-Aminoisoquinol-7′-yl)-3-propyl-5-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 526 (M+H, 100).mp 175° C.

Example 981-(1′-Aminoisoguinol-7′-yl)-3-ethyl-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 531 (M+H, 100); mp 161° C.

Example 991-(1′-Aminoisoquinol-7′-yl)-3-ethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 530 (M+H, 100); mp 135° C.

Example 1001-(1′-Aminoisoquinol-7′-yl)-3-ethyl-5-[4-(N-pyrrolidinocarbonyl-1-yl)phenylaminocarbonyl]pyrazolemesylate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 455 (M+H, 100).

Example 1011-(1′-Aminoisoquinol-7′-yl)-3-trifluoromethyl-5-[4-(imidazol-1′-yl)phenylaminocarbonyl]pyrazolebistrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 464 (M+H, 100); mp 115° C.

Example 1021-(1′-Aminoisoquinol-7′-yl)-3-trifluoromethyl-5-[3-fluoro-4-(2-methylimidazol-1′-yl)phenylaminocarbonyl]pyrazolebistrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 496 (M+H, 100); mp 115° C.

Example 1031-(1′-Aminoisoquinol-7′-yl)-3-trifluoromethyl-5-[4-(2-methylimidazol-1′-yl)phenylaminocarbonyl]pyrazolebistrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 478 (M+H, 100); mp 148° C.

Example 1041-(1′-Aminoisoquinol-7′-yl)-3-trifluoromethyl-5-[2-fluoro-4-(2-methylimidazol-1′-yl)phenylaminocarbonyl]pyrazolebistrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 496 (M+H, 100).

Example 1051-(3′-Aminobenzisoxazol-5′-yl)-3-methyl-5-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 488 (M+H, 100).

Example 1061-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 561 (M+H, 100); mp 155° C.

Example 1071-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[2-fluoro-4-(N-pyrrolidinocarbonyl,phenyl-aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 503 (M+H, 100); mp 150° C.

Example 1081-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(5-(2′-aminosulfonylphenyl)pyrid-2-yl)aminocarbonyl]pyrazolebistrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 544 (M+H, 100); mp 222° C.

Example 1091-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(5-(2′-methylsulfonylphenyl)pyrimid-2-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 544 (M+H, 100); mp 175° C.

Example 1101-(3′-Aminobenzisoxazol-5′-yl)-3-methyl-5-[(4-(pyrid-3′-yl)phenyl)aminocarbonyl]pyrazolebistrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 411 (M+H, 100); mp 142° C.

Example 1111-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(4-(pyrid-3′-yl-3-fluorophenyl)aminocarbonyl]pyrazolebistrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 483 (M+H, 100); mp 201° C.

Example 1121-(3′-Aminoindazol-5′-yl)-3-trifluoromethyl-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 560 (M+H, 100).

Example 1131-(3′-Aminoindazol-5′-yl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 559 (M+H, 100).

Example 1141-(3′-Aminoindazol-5′-yl)-3-trifluoromethyl-5-[2-fluoro-4-(N-pyrrolidinocarbonyl)phenylaminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 502 (M+H, 100); mp 166° C.

Example 1151-(3′-Aminoindazol-5′-yl)-3-methyl-5-[(4-(pyrid-3′-yl)phenyl)aminocarbonyl]pyrazole

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 410 (M+H, 100); mp 301° C.

Example 1161-(3′-Aminoindazol-5′-yl)-3-trifluoromethyl-5-[(4-(pyrid-3′-yl-3-fluorophenyl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound was prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 482 (M+H, 100); mp 190° C.

Example 1171-(3′-Aminomethylnaphth-2′-yl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole

3-Hydrazino-2-naphthoic acid: To 3-amino-2-naphthoic acid (15 g, 66.8mmol) in conc. HCl (100 ml) and water (100 ml) at 0° C. was added NaNO₂(9.22 g, 69 mmol) in 1 g portions while maintaing the reactiontemperature below 0° C. After 30 min below 0° C., SnCl₂.H₂O (75 g) wasadded in portions over 20 min. The ice bath was removed and stirred atambient temperature for 1 h. Reaction was filtered and the filter cakewashed with water and air dried. The crude material containing tin (II)salts was used as is and gave a mp>300° C.

5-(Furan-2-yl)-3-trifluoromethyl-1-(3-carboxynaphth-2-yl)-1H-pyrazole: Amixture of 1,1,1-trifluoro-4-(furan-2-yl)-2,4-butadione (4.2 g, 20.4mmol) and the hydrazine prepared above (6.66 g) in MeOH (150 ml) and TFA(2.32 g, 20.4 mmol) was stirred at ambient temperature for 5 days. Thereaction was evaporated and redissolved in EtOAc and washed with 1N HCl.The EtOAc solution was dried (MgSO₄) and evaporated to give 5.0 g ofmaterial. The desired product was isolated by MPLC on 300 g of flashsilica gel using a gradient of 1% MeOH in CHCl₃ to 3% MeOH in CHCl₃.

Fractions were collected in 25 mL portions with fractions 1–100 elutedwith 1% MeOH in CHCl₃, fractions 101–300 eluted with 2% MeOH in CHCl₃and fractions 301–500 eluted with 3% MeOH in CHCl₃. The title compound(1.52 g) was recovered from fractions 201–500; LRMS (M+H)⁺ m/z: 373.2.

5-(Furan-2-yl)-3-trifluoromethyl-1-(3′-hydroxymethylnaphth-2′-yl)-1H-pyrazole:To 1.52 g of5-(furan-2-yl)-3-trifluoromethyl-1-(3′-carboxynaphth-2′-yl)-1H-pyrazole(4.1 mmol) in THF (100 ml) at 0° C. was added N-methylmorpholine (4.5mmol, 0.46 g) followed by isobutylchloroformate (4.5 mmol, 0.62 g). Thereaction was maintained at 0° C. for 1 h then filtered into a solutionof NaBH₄ (12.3 mmol, 0.47 g) in water (50 ml) at 0° C. The THF wasremoved by evaporation, then the residue partioned between EtOAc and 1NHCl. The EtOAc layer was dried and evaporated to give 1.57 g of thebenzyl alcohol; LRMS (M+Na)⁺ m/z: 381.1.

5-(Furan-2-yl)-3-trifluoromethyl-1-(3′-azidomethylnaphth-2′-yl)-1H-pyrazole:To5-(furan-2-yl)-3-trifluoromethyl-1-(3′-hydroxymethylnaphthal-2′-yl)-1H-pyrazole(4.4 mmol, 1.57 g) and N-methylmorpholine (4.8 mmol, 0.49 g) in CH₂Cl₂(100 ml) at 0° C. was added methanesulfonyl chloride (4.8 mmol, 0.55 g)in CH₂Cl₂ (20 ml). The reaction was allowed to thaw to ambienttemperature over 5 h. The reaction was then washed with cold 1N HCl,dried (MgSO₄) and evaporated to give 1.82 g of the mesylate. Thismaterial was immediately dissolved in DMF (20 ml) and sodium azide (13.2mmol, 0.92 g) added. The reaction was stirred for 18 h, then dilutedwith brine and extracted with EtOAc. The EtOAc extract was washed withbrine (5×'s), dried (MgSO₄) and evaporated to give 1.37 g of crudeproduct. This material was purified to homogeneity by MPLC on a 360 gcolumn of flash silica by eluting with 10:1 hexane: EtOAc. Fractionswere collected in 25 ml portions and 0.75 g of5-(furan-2-yl)-3-trifluoromethyl-1-(3′-azidomethylnaphth-2′-yl)-1H-pyrazolewas recovered from fractions 68–100; LRMS (M+H)⁺ m/z: 384.0, (M+Na)⁺m/z: 406.1.

3-Trifluoromethyl-1-(3′-azidomethylnaphth-2′-yl)-1H-pyrazole-5-carboxylicacid: To an acetone (50 ml) solution of5-(furan-2-yl)-3-trifluoromethyl-1-(3′-azidomethylnaphth-2′-yl)-1H-pyrazole(1.98 mmol, 0.75 g) heated to 60° C. was added dropwise KMnO₄ (13.8mmol, 2.2 g) in water (40 ml) After TLC (5:1 Hexane: EtOAc) indicatedthat all of the starting material was consumed (ca. 4 h) the reactionwas cooled to ambient temperature and filtered through a pad of Celite®.The pad was washed thoroughly with acetone then the combined filtratewas condensed to remove the acetone. The remaining water suspension wasmade basic with 1N NaOH (pH 11) and the resulting solution washed withEt₂O. The basic solution was acidified with 1N HCl (pH 2) and extractedwith EtOAc. The extracts were dried and evaporated to give the titleacid (0.54 g); LRMS (M−H)⁻ m/z: 360.

1-(3′-Azidomethylnaphth-2′-yl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole:1-(3′-azidomethylnaphth-2′-yl)-3-trifluoromethyl-1H-pyrazole-5-carboxylicacid (1.5 mmol, 0.54 g) in CH₂Cl₂ (25 ml) was stirred with 1.5 ml of a2M solution of oxalyl chloride in CH₂Cl₂ (3 mmol) and a 2 drops of DMFfor 18 h. The reaction was evaporated and pumped on for several hours toremove the last traces of reagent to give 0.59 g of acid chloride. Theacid chloride was combined with2-fluoro-4-(2-methanesulfonylphenyl)aniline (1.7 mmol, 0.50 g) and DMAP(4.5 mmol, 0.55 g) in CH₂Cl₂ (25 ml) and stirred at ambient temperaturefor 18 h. The reaction mixture was evaporated and applied to a column offlash silica gel (200 g) and eluted with 3:1 hexane: EtOAc. There wasobtained 0.19 g of the title compound; LRMS (M−H)⁻ m/z: 607.

1-(3′-Aminomethylnaphth-2′-yl)-3-trifluoromethyl-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole:3-Trifluoromethyl-1-(3′-azidomethylnaphth-2′-yl)-1H-pyrazole-5-(N-(3-fluoro-2-methylsulfonyl-[1,1′]-biphen-4-yl)carboxyamide(0.31 mmol, 0.19 g) and SnCl₂.H₂O (1.25 mmol, 0.28 g) in MeOH (20 ml)was stirred at ambient temperature 18 h. The reaction was evaporated,taken up in 1N NaOH (50 ml), then extracted with EtOAc. The extractswere dried (MgSO₄) and evaporated. Purification of the final product wasby hplc utilizing gradient elution with a mixture of water:acetonitrilewith 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) columngave a pure sample of the title compound; LRMS (M+H)⁺ m/z: 583.

Example 1181-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-2′-hydroxymethyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 510 (M−H).

Example 1191-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-2′-methylaminomethyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 525 (M+H, 100).

Example 1201-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(2′-bromomethyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 574 (M+H, 100).

Example 1211-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-2′-pyridiniummethyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 573 (M+H, 100).

Example 1221-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(2′-aminomethyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 511 (M+H, 100).

Example 1231-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 565 (M+H, 100).

Example 1241-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-2′-imidazol-1″-yl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 562 (M+H, 100).

Example 1251-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[((2′-(4″-t-butoxycarbonyl)piperazin-1″-ylmethyl)-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 680 (M+H, 100).

Example 1261-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[((2′-(N,N-dimethylamino)pyridiniummethyl)-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 616 (M+H, 100).

Example 1271-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-2′-piperazin-1″-ylmethyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 580 (M+H, 100).

Example 1281-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-2′-N-methylmorpholiniummethyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 695 (M+H, 100).

Example 1291-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-2′-morpholinomethyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 581 (M+H, 100).

Example 1301-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(3-fluoro-2′-(N-methyl-N-methoxyamino)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 555 (M+H, 100).

Example 1311-(3′-Aminobenzisoxazol-5′-yl)-5-[(2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]triazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 493 (M+H, 100).

Example 1321-(3′-Aminobenzisoxazol-5′-yl)-5-[(2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]triazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 494 (M+H, 100).

Example 1331-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-5-[(2′-methylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazoletrifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 575 (M+H, 100).

Example 1341-(3′-Aminobenzisoxazol-5′-yl)-5-[(2′-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]tetrazolebis-trifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 473.3 (M+H, 100).

Example 1351-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[(2′-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazolebis-trifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 499.3 (M+H, 100).

Example 1361-(3′-Aminobenzisoxazol-5′-yl)-3-ethyl-5-[4′-(2″-dimethylaminomethylimidazol-1″-yl)-2′-fluorophenyl)aminocarbonyl]pyrazolebis-trifluoroacetate

The title compound is prepared in an analogous fashion. ESI massspectrum z (rel. intensity) 489.3 (M+H, 100).

TABLE 1

Ring Ex D—E H R^(1a) A—B MS 1 1′-Amino- pzl-a Me 2′-NH₂SO₂-[1,1′]- 499isoquinol-7′-yl biphen-4-yl 2 1′-Amino- pzl-a Me 2′-CH₃SO₂-[1,1′]- 498isoquinol-7′-yl biphen-4-yl 3 4′-amino- pzl-a Me 2′-NH₂SO₂-[1,1′]- 499isoquinol-7′-yl biphen-4-yl 4 isoquinol-7′-yl pzl-a Me 2′-NH₂SO₂-[1,1′]-484 biphen-4-yl 5 1′-Amino- isox Me 2′-NH₂SO₂-[1,1′]- 502isoquinol-7′-yl biphen-4-yl 6 isoquinol-5′-yl isox Me 2′-NH₂SO₂-[1,1′]-487 biphen-4-yl 7 isoquinol-7′-yl isox Me 2′-NH₂SO₂-[1,1′]- 487biphen-4-yl 8 2′-amino- isox Me 2′-NH₂SO₂-[1,1′]- 491 benzimidazol-biphen-4-yl 5′-yl 9 3′-aminoindazol- isox Me 2′-NH₂SO₂-[1,1′]- 491 5-ylbiphen-4-yl 10 3′-amino- isox Me 2′-NH₂SO₂-[1,1′]- 492 benzisoxazol-biphen-4-yl 5-yl 11 3′-amino- pzl-a Me 2′-NH₂SO₂-[1,1′]- 489benzisoxazol- biphen-4-yl 5-yl 12 1′-Amino- trz — 2′-NH₂SO₂-[1,1′]- 486isoquinol-7′-yl biphen-4-yl 13 4′-amino- trz — 2′-NH₂SO₂-[1,1′]- 486isoquinol-7′-yl biphen-4-yl 14 isoquinol-7′-yl trz — 2′-NH₂SO₂-[1,1′]-476 biphen-4-yl 15 quinol-2′-yl pzl-a Me 2′-NH₂SO₂-[1,1′]- 484biphen-4-yl 16 quinol-2′-yl pzl-b Me 2′-NH₂SO₂-[1,1′]- 484 biphen-4-yl17 3′-amino- pzl-a Me 2′-NH₂SO₂-[1,1′]- 488 indazol-5-yl biphen-4-yl 183′- pzl-a Me 2′-NH₂SO₂-[1,1′]- 488 aminoindazol-5-yl biphen-4-yl 193′-amino- pzl-a Me 5-(2′-NH₂SO₂- 490 benzisoxazol- phenyl)pyrid-2-yl5-yl 20 3′-amino- pzl-a Me isoquin-7-yl 385 benzisoxazol- 5-yl 211′-Amino- pzl-a Et 2′-NH₂SO₂-[1,1′]- 513 isoquinol-7′-yl biphen-4-yl 221′-Amino- pzl-a i-Pr 2′-NH₂SO₂-[1,1′]- 527 isoquinol-7′-yl biphen-4-yl23 2′,4′-diamino- pzl-a Me 2′-NH₂SO₂-[1,1′]- 515 quinazol-7′-ylbiphen-4-yl 24 4′-amino- pzl-a Me 2′-NH₂SO₂-[1,1′]- 500 quinazol-7′-ylbiphen-4-yl 25 1′-Amino- pzl-a Me 4-(N-pyrrolidinyl- 441 isoquinol-7′-ylcarbonyl)phenyl 26 3′-amino- pzl-a CF₃ 3-F-2′-CH₃SO₂- 501 benzisoxazol-[1,1′]-biphen-4-yl 5′-yl 27 1′-Amino- pzl-a CH₃ 2′-NH₂SO₂-[1,1′]- 500pthalazin-7′-yl biphen-4-yl 28 3′-amino- isox CH₃SO₂NH 5-(2′-NH₂SO₂- 586benzisoxazol- —CH₂ phenyl)pyrid-2-yl 29 3′-amino- pzl-a CF₃ 2-F-4- 491benzisoxazol- morpholinophenyl 5′-yl 30 3′-amino- pzl-a CF₃2-iPr-imidazol- 496 benzisoxazol- 1′-ylphenyl 5′-yl 31 3′-amino- pzl-aCF₃ 2′-Et-imidazol-1′- 482 benzisoxazol-5′-yl ylphenyl 32 3′-amino-pzl-a CF₃ 2′-(CH₃)₂NCH₂- 511 benzisoxazol-5′-yl imidazol-1′- ylphenyl 333′-amino- pzl-a CF₃ 2′-CH₃OCH₂- 498 benzisoxazol-5′-yl imidazol-1′-ylphenyl 34 3′-amino- pzl-a CF₃ 2-F-2′- 529 benzisoxazol-5′-yl(CH₃)₂NCH₂- imidazol-1′- ylphenyl 35 3′-amino- pzl-a CF₃ 2-CH₃O-2′-CH₃-498 benzisoxazol-5′-yl imidazol-1′- ylphenyl 36 3′-amino- pzl-a CF₃2-F-2′-iPr- 514 benzisoxazol-5′-yl imidazol-1′- ylphenyl 37 3′-amino-pzl-a CF₃ 2-F-2′-Et- 500 benzisoxazol-5′-yl imidazol-1′- ylphenyl 383′-amino- pzl-a Et 2-F-2′-Et- 460 benzisoxazol-5′-yl imidazol-1′-ylphenyl 39 3′-amino- pzl-a Et 2′-CH₃OCH₂- 458 benzisoxazol-5′-ylimidazol-1′- ylphenyl 40 3′-amino- pzl-a Et 2′-(CH₃)₂NCH₂- 471benzisoxazol-5′-yl imidazol-1′- ylphenyl 41 3′-amino- pzl-a Et 2′-CH₃-478 benzisoxazol-5′-yl benzimidazol-1′- ylphenyl 42 3′-amino- pzl-a Et2′-Et-imidazol-1′- 442 benzisoxazol-5′-yl ylphenyl 43 3′-amino- pzl-a Et2,5-diF-2′-Et- 464 benzisoxazol-5′-yl imidazol-1′- ylphenyl 44 3′-amino-pzl-a Et 2-F-4- 451 benzisoxazol-5′-yl morpholinophenyl 45 3′-amino-pzl-a Et 2′-iPr-imidazol- 456 benzisoxazol-5′-yl 1′-ylphenyl 463′-amino- pzl-a Et 2-F-2′-CH₃- 446 benzisoxazol-5′-yl imidazol-1′-ylphenyl 47 3′-amino- pzl-a Et 3-NH₂-2′- S40 benzisoxazol-5′-yl NH₂SO₂-[1,1′]-biphen-4-yl 48 3′-amino- pzl-a Et 3-NO₂-2′- 548benzisoxazol-5′-yl NH₂SO₂- [1,1′]-biphen-4-yl 49 3′-amino- pzl-a Et2′-CH₃-imidazol- 428 benzisoxazol-5′-yl 1′-ylphenyl 50 3′-amino- pzl-aEt 2-(CH₃)₂N-4-(N- 488 benzisoxazol-5′-yl pyrrolidino- carbonyl)phenyl51 3′-amino- pzl-a Et 2-pyrrolidino-4- 514 benzisoxazol-5′-yl(N-pyrrolidino- carbonyl)phenyl 52 3′-amino- pzl-a Et 2-F-4-(N- 463benzisoxazol-5′-yl pyrrolidino- carbonyl)phenyl 53 3′-amino- pzl-a Et3-F-2′-NH₂SO₂- 542 benzisoxazol-5′-yl [1,1′]-biphen-4-yl 54 3′-amino-pzl-a Et 5-(2′-CH₃SO₂- 525 benzisoxazol-5′-yl phenyl)pyrimid- 2-yl 553′-amino- pzl-a Et 3-F-2′-CH₃SO₂- 542 benzisoxazol-5′-yl[1,1′]-biphen-4-yl 56 3′-amino- pzl-a Et 5-(2′-NH₂SO₂- 502benzisoxazol-5′-yl phenyl)pyrid-2-yl 57 3′-amino- tzl — 3-F-2′-CH₃SO₂-494 benzisoxazol-5′-yl [1,1′]-biphen-4-yl 58 3′-amino- tzl —2′-CH₃-imidazol- 402 benzisoxazol-5′-yl 1′-ylphenyl 59 3′-amino- tzl —2′-NH₂SO₂-[1,1′]- 475 benzisoxazol-5′-yl biphen-4-yl 60 3′-amino- tzl —2-F-4-(N- 437 benzisoxazol-5′-yl pyrrolidino- carbonyl)phenyl 613′-amino- tzl — 2-pyrrolidino-4- 488 benzisoxazol-5′-yl (N-pyrrolidino-carbonyl)phenyl 62 1′-Amino- tzl — 3-F-2′-NH₂SO₂- 505 isoquinol-7′-yl[1,1′]-biphen-4-yl 63 1′-Amino- tzl — 3-F-2′-CH₃SO₂- 504 isoquinol-7′-yl[1,1′]-biphen-4-yl 64 1′-Amino- pzl-a CF₃ 5-(2′-NH₂SO₂- 545benzisoxazol-5′-yl phenyl)pyrimid- 2-yl 65 1′-Amino- pzl-a CF₃2′-CH₃-imidazol- 468 benzisoxazol-5′-yl 1′-ylphenyl 66 1′-Amino- pzl-aCF₃ 2-F-2′-CH₃- 486 benzisoxazol-5′-yl imidazol-1′- ylphenyl 671′-Amino- pzl-a CF₃ 2-F-1′-CH₃- 486 benzisoxazol-5′-yl imidazol-2′-ylphenyl 68 1′-Amino- pzl-a CF₃ 2′-NH₂-imidazol- 469 benzisoxazol-5′-yl1′-ylphenyl 69 1′-Amino- pzl-a CF₃ 2′-(CH₃)₂NCH₂- 539 benzisoxazol-5′-yl3-F-[1,1′]-biphen- 4-yl 70 1′-Amino- pzl-a CO₂Et 3-F-2′-NH₂SO₂- 565benzisoxazol-5′-yl [1,1′]-biphen-4-yl 71 1′-Amino- pzl-a CO₂H3-F-2′-NH₂SO₂- 537 benzisoxazol-5′-yl [1,1′]-biphen-4-yl 72 1′-Amino-pzl-a CONH₂ 3-F-2′-NH₂SO₂- 536 benzisoxazol-5′-yl [1,1′]-biphen-4-yl 731′-Amino- pzl-a CO₂Et 3-F-2′-CH₃SO₂- 564 benzisoxazol-5′-yl[1,1′]-biphen-4-yl 74 1′-Amino- pzl-a CO₂H 3-F-2′-CH₃SO₂- 534benzisoxazol-5′-yl [1,1′]-biphen-4-yl 75 1′-Amino- pzl-a CH₂OH3-F-2′-CH₃SO₂- 522 benzisoxazol-5′-yl [1,1′]-biphen-4-yl 76 1′-Amino-pzl-a (CH₃)₂N— 3-F-2′-CH₃SO₂- 549 benzisoxazol-5′-yl CH₂[1,1′]-biphen-4-yl 77 1′-Amino- pzl-c CO₂Et 3-F-2′-CH₃SO₂- 564benzisoxazol-5′-yl [1,1′]-biphen-4-yl 78 1′-Amino- pzl-c CO₂H3-F-2′-CH₃SO₂- 534 benzisoxazol-5′-yl [1,1′]-biphen-4-yl 79 1′,2′,3′,4′-pzl-a CH₃ 2′-NH₂SO₂-[1,1′]- 488 tetrahydro- biphen-4-yl isoquinol-7′-yl80 1′-Amino- pzl-b CH₃ 2′-CH₃NHSO₂- 513 isoquinol-7′-yl[1,1′]-biphen-4-yl 81 4′-amino- pzl-a CH₃ 2′-CH₃SO₂-[1,1′]- 498isoquinol-7′-yl biphen-4-yl 82 1′-Amino- pzl-a CF₃ 2′-CH₃SO₂-[1,1′]- 552isoquinol-7′-yl biphen-4-yl 83 1′-Amino- pzl-a CF₃ 2-F-4-(N- 513isoquinol-7′-yl pyrrolidino- carbonyl)phenyl 84 1′-Amino- pzl-a CF₃3-F-2′-CH₃SO₂- 570 isoquinol-7′-yl [1,1′]-biphen-4-yl 85 1′-Amino- pzl-aCF₃ 2′-NH₂SO₂-[1,1′]- 553 isoquinol-7′-yl biphen-4-yl 86 1′-Amino- pzl-aCF₃ 3-F-2′-NH₂SO₂- 571 isoquinol-7′-yl [1,1′]-biphen-4-yl 87 1′-Amino-pzl-a CF₃ 5-(2′-CH₃SO₂- 553 isoquinol-7′-yl phenyl)pyrid-2-yl 881′-Amino- pzl-a CH₃ 3-F-2′-NH₂SO₂- 517 isoquinol-7′-yl[1,1′]-biphen-4-yl 89 1′-Amino- pzl-a CH₃ 3-F-2′-CH₃SO₂- 516isoquinol-7′-yl [1,1′]-biphen-4-yl 90 1′-Amino- pzl-a CF₃2′-NH₂SO₂-3-Cl- 587 isoquinol-7′-yl [1,1′]-biphen-4-yl 91 1′-Amino-pzl-a CF₃ 2′-NH₂SO₂-3- 567 isoquinol-7′-yl CH₃- [1,1′]-biphen-4-yl 921′-Amino- pzl-a CF₃ 2′-CH₃NHSO₂- 567 isoquinol-7′-yl [1,1′]-biphen-4-yl93 1′-Amino- pzl-a Et 2′-CH₃NHSO₂- 527 isoquinol-7′-yl[1,1′]-biphen-4-yl 94 1′-Amino- pzl-a Et 2′-CH₃SO₂-[1,1′]- 512isoquinol-7′-yl biphen-4-yl 95 1′-Amino- pzl-a n-Pr 2′-NH₂SO₂-[1,1′]-527 isoquinol-7′-yl biphen-4-yl 96 1′-Amino- pzl-a n-Pr 2′-CH₃NHSO₂- 541isoquinol-7′-yl [1,1′]-biphen-4-yl 97 1′-Amino- pzl-a n-Pr2′-CH₃SO₂-[1,1′]- 526 isoquinol-7′-yl biphen-4-yl 98 1′-Amino- pzl-a Et3-F-2′-NH₂SO₂- 531 isoquinol-7′-yl [1,1′]-biphen-4-yl 99 1′-Amino- pzl-aEt 3-F-2′-CH₃SO₂- 530 isoquinol-7′-yl [1,1′]-biphen-4-yl 100 1′-Amino-pzl-a Et N-pyrrolidino- 455 isoquinol-7′-yl carbonyl 101 1′-Amino- pzl-aCF₃ 4-(imidazol-1′-yl) 464 isoquinol-7′-yl phenyl 102 1′-Amino- pzl-aCF₃ 3-F-2′-CH₃- 496 isoquinol-7′-yl imidazol-1′- ylphenyl 103 1′-Amino-pzl-a CF₃ 2′-CH₃-imidazol- 478 isoquinol-7′-yl 1′-ylphenyl 104 1′-Amino-pzl-a CF₃ 2-F-2′-CH₃- 496 isoquinol-7′-yl imidazol-1′- ylphenyl 1053′-amino- pzl-a CH₃ 2′-CH₃SO₂-[1,1′]- 488 benzisoxazol-5′-yl biphen-4-yl106 3′-amino- pzl-a CF₃ 3-F-2′-NH₂SO₂- 561 benzisoxazol-5′-yl[1,1′]-biphen-4-yl 107 3′-amino- pzl-a CF₃ 2-F-4-(N- 503benzisoxazol-5′-yl pyrrolidino- carbonyl)phenyl 108 3′-amino- pzl-a CF₃5-(2′-NH₂SO₂- 544 benzisoxazol-5′-yl phenyl)pyrid-2-yl 109 3′-amino-pzl-a CF₃ 5-(2′-CH₃SO₂- 544 benzisoxazol-5′-yl phenyl)pyrimid- 2-yl 1103′-amino- pzl-a CH₃ pyrid-3′-yl-phenyl 411 benzisoxazol-5′-yl 1113′-amino- pzl-a CF₃ 2-F-pyrid-2′-yl- 483 benzisoxazol-5′-yl phenyl 1123′-amino- pzl-a CF₃ 3-F-2′-NH₂SO₂- 560 indazol-5′-yl [1,1′]-biphen-4-yl113 3′-amino- pzl-a CF₃ 3-F-2′-CH₃SO₂- 559 indazol-5′-yl[1,1′]-biphen-4-yl 114 3′-amino- pzl-a CF₃ 2-F-4-(N- 502 indazol-5′-ylpyrrolidino- carbonyl)phenyl 115 3′-amino- pzl-a CH₃ pyrid-3′-yl-phenyl410 indazol-5′-yl 116 3′-amino- pzl-a CF₃ 2-F-pyrid-2′-yl- 482indazol-5′-yl phenyl 117 3′-aminomethyl- pzl-a CF₃ 3-F-2′-CH₃SO₂- 583naphthal-2′-yl [1,1′]-biphen-4-yl 118 3′-amino- pzl-a CF₃ 3-F-2′-HOCH₂-510 benzisoxazol-5′-yl [1,1′]-biphen-4-yl (M- H) 119 3′-amino- pzl-a CF₃3-F-2′-(N- 525 benzisoxazol-5′-yl methylamino- methyl)-[1,1′]-biphen-4-yl 120 3′-amino- pzl-a CF₃ 3-F-2′- 574 benzisoxazol-5′-ylbromomethyl- [1,1′]-biphen-4-yl 121 3′-amino- pzl-a CF₃ 3-F-2′-(N- 573benzisoxazol-5′-yl pyridinium- methyl)-[1,1′]- biphen-4-yl 122 3′-amino-pzl-a CF₃ 3-F-2′- 511 benzisoxazol-5′-yl aminomethyl- [1,1′]-biphen-4-yl123 3-amino- pzl-a CF₃ 3-F-2′-(N- 565 benzisoxazol-5′-yl pyrrolidinyl-methyl)-[1,1′]- biphen-4-yl 124 3′-amino- pzl-a CF₃ 3-F-2′-(N- 562benzisoxazol-5′-yl imidazol-1- ylmethyl)-[1,1′]- biphen-4-yl 1253-amino- pzl-a CF₃ 3-F-2′-(1″N-(4″N- 680 benzisoxazol-5′-yl t-butoxycarbonyl)- piperazinyl- methyl)-[1,1′]- biphen-4-yl 126 3′-amino-pzl-a CF₃ 3-F-2′-(N-(4″- 616 benzisoxazol-5′-yl N,N- dimethylamino)-pyridinium- methyl)-[1,1′]- biphen-4-yl 127 3′-amino- pzl-a CF₃3-F-2′-(1″N- 580 benzisoxazol-5′-yl piperazinyl- methyl)-[1,1′]-biphen-4-yl 128 3′-amino- pzl-a CF₃ 3-F-2′-(1″N- 695 benzisoxazol-5′-ylmethyl-1″N- morpholinium)- methyl)-(1,1′]- biphen-4-yl 129 3′-amino-pzl-a CF₃ 3-F-2′-(N- 581 benzisoxazol-5′-yl morpholino- methyl)-[1,1′]-biphen-4-yl 130 3′-amino- pzl-a CF₃ 3-F-2′-((N- 555benzisoxazol-5′-yl methyl-N- methoxy)- aminomethyl)- [1,1′]-biphen-4-yl131 3′-amino- trz — 3-F-2′-CH₃SO₂- 493 benzisoxazol-5′-yl[1,1′]-biphen-4-yl 132 3′-amino- trz — 3-F-2′-H₂NSO₂- 494benzisoxazol-5′-yl [1,1′]-biphen-4-yl 133 3′-amino- pzl-a CF₃ 3-F-2′-575 benzisoxazol-5′-yl CH₃NHSO₂- [1,1′]-biphen-4-yl 134 3′-amino- tzl —2′-(CH₃)₂NCH₂- 473 benzisoxazol-5′-yl 3-F- [1,1′]-biphen-4-yl 1353′-amino- pzl-a CH₃CH₂ 2′-(CH₃)₂NCH₂- 499 benzisoxazol-5′-yl 3-F-[1,1′]-biphen-4-yl 136 3′-amino- pzl-a CH₃CH₂ 2-F-(2′- 489benzisoxazol-5′-yl (CH₃)₂NCH₂- imidazol-1′- yl)phenyl

The following tables contain representative examples of the presentinvention. Each entry in each table is intended to be paired with eachformulae at the start of the table. For example, example 1 in Table 2 isintended to be paired with each of formulae a₁–y₉.

TABLE 2

a₁ R^(1a) = CH₃ a₂ R^(1a) = CF₃ a₃ R^(1a) = SCH₃ a₄ R^(1a) = SOCH₃ a₅R^(1a) = SO₂CH₃ a₆ R^(1a) = Cl a₇ R^(1a) = Br a₈ R^(1a) = CO₂CH₃ a₉R^(1a) = CH₂OCH₃

b₁ R^(1a) = CH₃ b₂ R^(1a) = CF₃ b₃ R^(1a) = SCH₃ b₄ R^(1a) = SOCH₃ b₅R^(1a) = SO₂CH₃ b₆ R^(1a) = Cl b₇ R^(1a) = Br b₈ R^(1a) = CO₂CH₃ b₉R^(1a) = CH₂OCH₃

c₁ R^(1a) = CH₃ c₂ R^(1a) = CF₃ c₃ R^(1a) = SCH₃ c₄ R^(1a) = SOCH₃ c₅R^(1a) = SO₂CH₃ c₆ R^(1a) = Cl c₇ R^(1a) = Br c₈ R^(1a) = CO₂CH₃ c₉R^(1a) = CH₂OCH₃

d₁ R^(1a) = CH₃ d₂ R^(1a) = CF₃ d₃ R^(1a) = SCH₃ d₄ R^(1a) = SOCH₃ d₅R^(1a) = SO₂CH₃ d₆ R^(1a) = Cl d₇ R^(1a) = Br d₈ R^(1a) = CO₂CH₃ d₉R^(1a) = CH₂OCH₃

e₁ R^(1a) = CH₃ e₂ R^(1a) = CF₃ e₃ R^(1a) = SCH₃ e₄ R^(1a) = SOCH₃ e₅R^(1a) = SO₂CH₃ e₆ R^(1a) = Cl e₇ R^(1a) = Br e₈ R^(1a) = CO₂CH₃ e₉R^(1a) = CH₂OCH₃

f₁ R^(1a) = CH₃ f₂ R^(1a) = CF₃ f₃ R^(1a) = SCH₃ f₄ R^(1a) = SOCH₃ f₅R^(1a) = SO₂CH₃ f₆ R^(1a) = Cl f₇ R^(1a) = Br f₈ R^(1a) = CO₂CH₃ f₉R^(1a) = CH₂OCH₃

g₁ R^(1a) = CH₃ g₂ R^(1a) = CF₃ g₃ R^(1a) = SCH₃ g₄ R^(1a) = SOCH₃ g₅R^(1a) = SO₂CH₃ g₆ R^(1a) = Cl g₇ R^(1a) = Br g₈ R^(1a) = CO₂CH₃ g₉R^(1a) = CH₂OCH₃

h₁ R^(1a) = CH₃ h₂ R^(1a) = CF₃ h₃ R^(1a) = SCH₃ h₄ R^(1a) = SOCH₃ h₅R^(1a) = SO₂CH₃ h₆ R^(1a) = Cl h₇ R^(1a) = Br h₈ R^(1a) = CO₂CH₃ h₉R^(1a) = CH₂OCH₃

i₁ R^(1a) = CH₃ i₂ R^(1a) = CF₃ i₃ R^(1a) = SCH₃ i₄ R^(1a) = SOCH₃ i₅R^(1a) = SO₂CH₃ i₆ R^(1a) = Cl i₇ R^(1a) = Br i₈ R^(1a) = CO₂CH₃ i₉R^(1a) = CH₂OCH₃

j₁ R^(1a) = CH₃ j₂ R^(1a) = CF₃ j₃ R^(1a) = SCH₃ j₄ R^(1a) = SOCH₃ j₅R^(1a) = SO₂CH₃ j₆ R^(1a) = Cl j₇ R^(1a) = Br j₈ R^(1a) = CO₂CH₃ j₉R^(1a) = CH₂OCH₃

k₁ R^(1a) = CH₃ k₂ R^(1a) = CF₃ k₃ R^(1a) = SCH₃ k₄ R^(1a) = SOCH₃ k₅R^(1a) = SO₂CH₃ k₆ R^(1a) = Cl k₇ R^(1a) = Br k₈ R^(1a) = CO₂CH₃ k₉R^(1a) = CH₂OCH₃

l₁ R^(1a) = CH₃ l₂ R^(1a) = CF₃ l₃ R^(1a) = SCH₃ l₄ R^(1a) = SOCH₃ l₅R^(1a) = SO₂CH₃ l₆ R^(1a) = Cl l₇ R^(1a) = Br l₈ R^(1a) = CO₂CH₃ l₉R^(1a) = CH₂OCH₃

m₁ R^(1a) = CH₃ m₂ R^(1a) = CF₃ m₃ R^(1a) = SCH₃ m₄ R^(1a) = SOCH₃ m₅R^(1a) = SO₂CH₃ m₆ R^(1a) = Cl m₇ R^(1a) = Br m₈ R^(1a) = CO₂CH₃ m₉R^(1a) = CH₂OCH₃

n₁ R^(1a) = CH₃ n₂ R^(1a) = CF₃ n₃ R^(1a) = SCH₃ n₄ R^(1a) = SOCH₃ n₅R^(1a) = SO₂CH₃ n₆ R^(1a) = Cl n₇ R^(1a) = Br n₈ R^(1a) = CO₂CH₃ n₉R^(1a) = CH₂OCH₃

o₁ R^(1a) = CH₃ o₂ R^(1a) = CF₃ o₃ R^(1a) = SCH₃ o₄ R^(1a) = SOCH₃ o₅R^(1a) = SO₂CH₃ o₆ R^(1a) = Cl o₇ R^(1a) = Br o₈ R^(1a) = CO₂CH₃ o₉R^(1a) = CH₂OCH₃

p₁ R^(1a) = CH₃ p₂ R^(1a) = CF₃ p₃ R^(1a) = SCH₃ p₄ R^(1a) = SOCH₃ p₅R^(1a) = SO₂CH₃ p₆ R^(1a) = Cl p₇ R^(1a) = Br p₈ R^(1a) = CO₂CH₃ p₉R^(1a) = CH₂OCH₃

q₁ R^(1a) = CH₃ q₂ R^(1a) = CF₃ q₃ R^(1a) = SCH₃ q₄ R^(1a) = SOCH₃ q₅R^(1a) = SO₂CH₃ q₆ R^(1a) = Cl q₇ R^(1a) = Br q₈ R^(1a) = CO₂CH₃ q₉R^(1a) = CH₂OCH₃

r₁ R^(1a) = CH₃ r₂ R^(1a) = CF₃ r₃ R^(1a) = SCH₃ r₄ R^(1a) = SOCH₃ r₅R^(1a) = SO₂CH₃ r₆ R^(1a) = Cl r₇ R^(1a) = Br r₈ R^(1a) = CO₂CH₃ r₉R^(1a) = CH₂OCH₃

s₁ R^(1a) = CH₃ s₂ R^(1a) = CF₃ s₃ R^(1a) = SCH₃ s₄ R^(1a) = SOCH₃ s₅R^(1a) = SO₂CH₃ s₆ R^(1a) = Cl s₇ R^(1a) = Br s₈ R^(1a) = CO₂CH₃ s₉R^(1a) = CH₂OCH₃

t₁ R^(1a) = CH₃ t₂ R^(1a) = CF₃ t₃ R^(1a) = SCH₃ t₄ R^(1a) = SOCH₃ t₅R^(1a) = SO₂CH₃ t₆ R^(1a) = Cl t₇ R^(1a) = Br t₈ R^(1a) = CO₂CH₃ t₉R^(1a) = CH₂OCH₃

u₁ R^(1a) = CH₃ u₂ R^(1a) = CF₃ u₃ R^(1a) = SCH₃ u₄ R^(1a) = SOCH₃ u₅R^(1a) = SO₂CH₃ u₆ R^(1a) = Cl u₇ R^(1a) = Br u₈ R^(1a) = CO₂CH₃ u₉R^(1a) = CH₂OCH₃

v₁ R^(1a) = CH₃ v₂ R^(1a) = CF₃ v₃ R^(1a) = SCH₃ v₄ R^(1a) = SOCH₃ v₅R^(1a) = SO₂CH₃ v₆ R^(1a) = Cl v₇ R^(1a) = Br v₈ R^(1a) = CO₂CH₃ v₉R^(1a) = CH₂OCH₃

w₁ R^(1a) = CH₃ w₂ R^(1a) = CF₃ w₃ R^(1a) = SCH₃ w₄ R^(1a) = SOCH₃ w₅R^(1a) = SO₂CH₃ w₆ R^(1a) = Cl w₇ R^(1a) = Br w₈ R^(1a) = CO₂CH₃ w₉R^(1a) = CH₂OCH₃

x₁ R^(1a) = CH₃ x₂ R^(1a) = CF₃ x₃ R^(1a) = SCH₃ x₄ R^(1a) = SOCH₃ x₅R^(1a) = SO₂CH₃ x₆ R^(1a) = Cl x₇ R^(1a) = Br x₈ R^(1a) = CO₂CH₃ x₉R^(1a) = CH₂OCH₃

y₁ R^(1a) = CH₃ y₂ R^(1a) = CF₃ y₃ R^(1a) = SCH₃ y₄ R^(1a) = SOCH₃ y₅R^(1a) = SO₂CH₃ y₆ R^(1a) = Cl y₇ R^(1a) = Br y₈ R^(1a) = CO₂CH₃ y₉R^(1a) = CH₂OCH₃ Ex # A B 1 phenyl 2-(aminosulfonyl)phenyl 2 phenyl2-(methylaminosulfonyl)phenyl 3 phenyl 1-pyrrolidinocarbonyl 4 phenyl2-(methylsulfonyl)phenyl 5 phenyl 4-morpholino 6 phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 7 phenyl 4-morpholinocarbonyl 8 2-pyridyl2-(aminosulfonyl)phenyl 9 2-pyridyl 2-(methylaminosulfonyl)phenyl 102-pyridyl 1-pyrrolidinocarbonyl 11 2-pyridyl 2-(methylsulfonyl)phenyl 122-pyridyl 4-morpholino 13 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 142-pyridyl 4-morpholinocarbonyl 15 3-pyridyl 2-(aminosulfonyl)phenyl 163-pyridyl 2-(methylaminosulfonyl)phenyl 17 3-pyridyl1-pyrrolidinocarbonyl 18 3-pyridyl 2-(methylsulfonyl)phenyl 19 3-pyridyl4-morpholino 20 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 21 3-pyridyl4-morpholinocarbonyl 22 2-pyrimidyl 2-(aminosulfonyl)phenyl 232-pyrimidyl 2-(methylaminosulfonyl)phenyl 24 2-pyrimidyl1-pyrrolidinocarbonyl 25 2-pyrimidyl 2-(methylsulfonyl)phenyl 262-pyrimidyl 4-morpholino 27 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl28 2-pyrimidyl 4-morpholinocarbonyl 29 5-pyrimidyl2-(aminosulfonyl)phenyl 30 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 315-pyrimidyl 1-pyrrolidinocarbonyl 32 5-pyrimidyl2-(methylsulfonyl)phenyl 33 5-pyrimidyl 4-morpholino 34 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 35 5-pyrimidyl 4-morpholinocarbonyl 362-Cl-phenyl 2-(aminosulfonyl)phenyl 37 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 38 2-Cl-phenyl 1-pyrrolidinocarbonyl 392-Cl-phenyl 2-(methylsulfonyl)phenyl 40 2-Cl-phenyl 4-morpholino 412-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 42 2-Cl-phenyl4-morpholinocarbonyl 43 2-F-phenyl 2-(aminosulfonyl)phenyl 44 2-F-phenyl2-(methylaminosulfonyl)phenyl 45 2-F-phenyl 1-pyrrolidinocarbonyl 462-F-phenyl 2-(methylsulfonyl)phenyl 47 2-F-phenyl 4-morpholino 482-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 49 2-F-phenyl4-morpholinocarbonyl 50 2,5-diF-phenyl 2-(aminosulfonyl)phenyl 512,5-diF-phenyl 2-(methylaminosulfonyl)phenyl 52 2,5-diF-phenyl1-pyrrolidinocarbonyl 53 2,5-diF-phenyl 2-(methylsulfonyl)phenyl 542,5-diF-phenyl 4-morpholino 55 2,5-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 56 2,5-diF-phenyl 4-morpholinocarbonyl 57phenyl 2-(N-pyrrolidinyl-methyl)phenyl 58 phenyl2-(N-piperidinyl-methyl)phenyl 59 phenyl 2-(N-morpholino-methyl)phenyl60 phenyl 2-(N,N′-methylmorpholinium-methyl)phenyl 61 phenyl2-(N-pyridinium-methyl)phenyl 62 phenyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 63 phenyl2-(N-azatanyl-methyl)phenyl 64 phenyl 2-(N-azetidinyl-methyl)phenyl 65phenyl 2-(N-piperazinyl-methyl)phenyl 66 phenyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 67 phenyl2-(N-imidazolyl-methyl)phenyl 68 phenyl2-(N-methoxy-N-methylamino-methyl)phenyl 69 phenyl2-(N-pyridonyl-methyl)phenyl 70 phenyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 71 phenyl2-(amidinyl)phenyl 72 phenyl 2-(N-guanidinyl)phenyl 73 phenyl2-(imidazolyl)phenyl 74 phenyl 2-(imidazolidinyl)phenyl 75 phenyl2-(2-imidazolidinyl-sulfonyl)phenyl 76 phenyl 2-(2-pyrrolidinyl)phenyl77 phenyl 2-(2-piperidinyl)phenyl 78 phenyl 2-(amidinyl-methyl)phenyl 79phenyl 2-(2-imidazolidinyl-methyl)phenyl 80 phenyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 81 phenyl2-dimethylaminoimidazol-1-yl 82 phenyl 2-(3-aminophenyl) 83 phenyl2-(3-pyrrolidinylcarbonyl) 84 phenyl 2-glycinoyl 85 phenyl2-(imidazol-1-ylacetyl) 86 2-pyridyl 2-(N-pyrrolidinyl-methyl)phenyl 872-pyridyl 2-(N-piperidinyl-methyl)phenyl 88 2-pyridyl2-(N-morpholino-methyl)phenyl 89 2-pyridyl2-(N,N′-methylmorpholinium-methyl)phenyl 90 2-pyridyl2-(N-pyridinium-methyl)phenyl 91 2-pyridyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 92 2-pyridyl2-(N-azatanyl-methyl)phenyl 93 2-pyridyl 2-(N-azetidinyl-methyl)phenyl94 2-pyridyl 2-(N-piperazinyl-methyl)phenyl 95 2-pyridyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 96 2-pyridyl2-(N-imidazolyl-methyl)phenyl 97 2-pyridyl2-(N-methoxy-N-methylamino-methyl)phenyl 98 2-pyridyl2-(N-pyridonyl-methyl)phenyl 99 2-pyridyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 100 2-pyridyl2-(amidinyl)phenyl 101 2-pyridyl 2-(N-guanidinyl)phenyl 102 2-pyridyl2-(imidazolyl)phenyl 103 2-pyridyl 2-(imidazolidinyl)phenyl 1042-pyridyl 2-(2-imidazolidinyl-sulfonyl)phenyl 105 2-pyridyl2-(2-pyrrolidinyl)phenyl 106 2-pyridyl 2-(2-piperidinyl)phenyl 1072-pyridyl 2-(amidinyl-methyl)phenyl 108 2-pyridyl2-(2-imidazolidinyl-methyl)phenyl 109 2-pyridyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 110 2-pyridyl2-dimethylaminoimidazol-1-yl 111 2-pyridyl 2-(3-aminophenyl) 1122-pyridyl 2-(3-pyrrolidinylcarbonyl) 113 2-pyridyl 2-glycinoyl 1142-pyridyl 2-(imidazol-1-ylacetyl) 115 3-pyridyl2-(N-pyrrolidinyl-methyl)phenyl 116 3-pyridyl2-(N-piperidinyl-methyl)phenyl 117 3-pyridyl2-(N-morpholino-methyl)phenyl 118 3-pyridyl2-(N,N′-methylmorpholinium-methyl)phenyl 119 3-pyridyl2-(N-pyridinium-methyl)phenyl 120 3-pyridyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 121 3-pyridyl2-(N-azatanyl-methyl)phenyl 122 3-pyridyl 2-(N-azetidinyl-methyl)phenyl123 3-pyridyl 2-(N-piperazinyl-methyl)phenyl 124 3-pyridyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 125 3-pyridyl2-(N-imidazolyl-methyl)phenyl 126 3-pyridyl2-(N-methoxy-N-methylamino-methyl)phenyl 127 3-pyridyl2-(N-pyridonyl-methyl)phenyl 128 3-pyridyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 129 3-pyridyl2-(amidinyl)phenyl 130 3-pyridyl 2-(N-guanidinyl)phenyl 131 3-pyridyl2-(imidazolyl)phenyl 132 3-pyridyl 2-(imidazolidinyl)phenyl 1333-pyridyl 2-(2-imidazolidinyl-sulfonyl)phenyl 134 3-pyridyl2-(2-pyrrolidinyl)phenyl 135 3-pyridyl 2-(2-piperidinyl)phenyl 1363-pyridyl 2-(amidinyl-methyl)phenyl 137 3-pyridyl2-(2-imidazolidinyl-methyl)phenyl 138 3-pyridyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 139 3-pyridyl2-dimethylaminoimidazol-1-yl 140 3-pyridyl 2-(3-aminophenyl) 1413-pyridyl 2-(3-pyrrolidinylcarbonyl) 142 3-pyridyl 2-glycinoyl 1433-pyridyl 2-(imidazol-1-ylacetyl) 144 2-pyrimidyl2-(N-pyrrolidinyl-methyl)phenyl 145 2-pyrimidyl2-(N-piperidinyl-methyl)phenyl 146 2-pyrimidyl2-(N-morpholino-methyl)phenyl 147 2-pyrimidyl2-(N,N′-methylmorpholinium-methyl)phenyl 148 2-pyrimidyl2-(N-pyridinium-methyl)phenyl 149 2-pyrimidyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 150 2-pyrimidyl2-(N-azatanyl-methyl)phenyl 151 2-pyrimidyl2-(N-azetidinyl-methyl)phenyl 152 2-pyrimidyl2-(N-piperazinyl-methyl)phenyl 153 2-pyrimidyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 154 2-pyrimidyl2-(N-imidazolyl-methyl)phenyl 155 2-pyrimidyl2-(N-methoxy-N-methylamino-methyl)phenyl 156 2-pyrimidyl2-(N-pyridonyl-methyl)phenyl 157 2-pyrimidyl2-(N-(N′,N-dimethylhydrazinyl-methyl)phenyl 158 2-pyrimidyl2-(amidinyl)phenyl 159 2-pyrimidyl 2-(N-guanidinyl)phenyl 1602-pyrimidyl 2-(imidazolyl)phenyl 161 2-pyrimidyl2-(imidazolidinyl)phenyl 162 2-pyrimidyl2-(2-imidazolidinyl-sulfonyl)phenyl 163 2-pyrimidyl2-(2-pyrrolidinyl)phenyl 164 2-pyrimidyl 2-(2-piperidinyl)phenyl 1652-pyrimidyl 2-(amidinyl-methyl)phenyl 166 2-pyrimidyl2-(2-imidazolidinyl-methyl)phenyl 167 2-pyrimidyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 168 2-pyrimidyl2-dimethylaminoimidazol-1-yl 169 2-pyrimidyl 2-(3-aminophenyl) 1702-pyrimidyl 2-(3-pyrrolidinylcarbonyl) 171 2-pyrimidyl 2-glycinoyl 1722-pyrimidyl 2-(imidazol-1-ylacetyl) 173 2-Cl-phenyl2-(N-pyrrolidinyl-methyl)phenyl 174 2-Cl-phenyl2-(N-piperidinyl-methyl)phenyl 175 2-Cl-phenyl2-(N-morpholino-methyl)phenyl 176 2-Cl-phenyl2-(N,N′-methylmorpholinium-methyl)phenyl 177 2-Cl-phenyl2-(N-pyridinium-methyl)phenyl 178 2-Cl-phenyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 179 2-Cl-phenyl2-(N-azatanyl-methyl)phenyl 180 2-Cl-phenyl2-(N-azetidinyl-methyl)phenyl 181 2-Cl-phenyl2-(N-piperazinyl-methyl)phenyl 182 2-Cl-phenyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 183 2-Cl-phenyl2-(N-imidazolyl-methyl)phenyl 184 2-Cl-phenyl2-(N-methoxy-N-methylamino-methyl)phenyl 185 2-Cl-phenyl2-(N-pyridonyl-methyl)phenyl 186 2-Cl-phenyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 187 2-Cl-phenyl2-(amidinyl)phenyl 188 2-Cl-phenyl 2-(N-guanidinyl)phenyl 1892-Cl-phenyl 2-(imidazolyl)phenyl 190 2-Cl-phenyl2-(imidazolidinyl)phenyl 191 2-Cl-phenyl2-(2-imidazolidinyl-sulfonyl)phenyl 192 2-Cl-phenyl2-(2-pyrrolidinyl)phenyl 193 2-Cl-phenyl 2-(2-piperidinyl)phenyl 1942-Cl-phenyl 2-(amidinyl-methyl)phenyl 195 2-Cl-phenyl2-(2-imidazolidinyl-methyl)phenyl 196 2-Cl-phenyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 197 2-Cl-phenyl2-dimethylaminoimidazol-1-yl 198 2-Cl-phenyl 2-(3-aminophenyl) 1992-Cl-phenyl 2-(3-pyrrolidinylcarbonyl) 200 2-Cl-phenyl 2-glycinoyl 2012-Cl-phenyl 2-(imidazol-1-ylacetyl) 202 2-F-phenyl2-(N-pyrrolidinyl-methyl)phenyl 203 2-F-phenyl2-(N-piperidinyl-methyl)phenyl 204 2-F-phenyl2-(N-morpholino-methyl)phenyl 205 2-F-phenyl2-(N,N′-methylmorpholinium-methyl)phenyl 206 2-F-phenyl2-(N-pyridinium-methyl)phenyl 207 2-F-phenyl2-(N-4-(N,N-dimethylamino)-pyridinium-methyl) phenyl 208 2-F-phenyl2-(N-azatanyl-methyl)phenyl 209 2-F-phenyl 2-(N-azetidinyl-methyl)phenyl210 2-F-phenyl 2-(N-piperazinyl-methyl)phenyl 211 2-F-phenyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 212 2-F-phenyl2-(N-imidazolyl-methyl)phenyl 213 2-F-phenyl2-(N-methoxy-N-methylamino-methyl)phenyl 214 2-F-phenyl2-(N-pyridonyl-methyl)phenyl 215 2-F-phenyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 216 2-F-phenyl2-(amidinyl)phenyl 217 2-F-phenyl 2-(N-guanidinyl)phenyl 218 2-F-phenyl2-(imidazolyl)phenyl 219 2-F-phenyl 2-(imidazolidinyl)phenyl 2202-F-phenyl 2-(2-imidazolidinyl-sulfonyl)phenyl 221 2-F-phenyl2-(2-pyrrolidinyl)phenyl 222 2-F-phenyl 2-(2-piperidinyl)phenyl 2232-F-phenyl 2-(amidinyl-methyl)phenyl 224 2-F-phenyl2-(2-imidazolidinyl-methyl)phenyl 225 2-F-phenyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 226 2-F-phenyl2-dimethylaminoimidazol-1-yl 227 2-F-phenyl 2-(3-aminophenyl) 2282-F-phenyl 2-(3-pyrrolidinylcarbonyl) 229 2-F-phenyl 2-glycinoyl 2302-F-phenyl 2-(imidazol-1-ylacetyl) 231 2,5-diF-phenyl2-(N-pyrrolidinyl-methyl)phenyl 232 2,5-diF-phenyl2-(N-piperidinyl-methyl)phenyl 233 2,5-diF-phenyl2-(N-morpholino-methyl)phenyl 234 2,5-diF-phenyl2-(N,N′-methylmorpholinium-methyl)phenyl 235 2,5-diF-phenyl2-(N-pyridinium-methyl)phenyl 236 2,5-diF-phenyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 237 2,5-diF-phenyl2-(N-azatanyl-methyl)phenyl 238 2,5-diF-phenyl2-(N-azetidinyl-methyl)phenyl 239 2,5-diF-phenyl2-(N-piperazinyl-methyl)phenyl 240 2,5-diF-phenyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 241 2,5-diF-phenyl2-(N-imidazolyl-methyl)phenyl 242 2,5-diF-phenyl2-(N-methoxy-N-methylamino-methyl)phenyl 243 2,5-diF-phenyl2-(N-pyridonyl-methyl) phenyl 244 2,5-diF-phenyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 245 2,5-diF-phenyl2-(amidinyl)phenyl 246 2,5-diF-phenyl 2-(N-guanidinyl)phenyl 2472,5-diF-phenyl 2-(imidazolyl)phenyl 248 2,5-diF-phenyl2-(imidazolidinyl)phenyl 249 2,5-diF-phenyl2-(2-imidazolidinyl-sulfonyl)phenyl 250 2,5-diF-phenyl2-(2-pyrrolidinyl)phenyl 251 2,5-diF-phenyl 2-(2-piperidinyl)phenyl 2522,5-diF-phenyl 2-(amidinyl-methyl)phenyl 253 2,5-diF-phenyl2-(2-imidazolidinyl-methyl)phenyl 254 2,5-diF-phenyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 255 2,5-diF-phenyl2-dimethylaminoimidazol-1-yl 256 2,5-diF-phenyl 2-(3-aminophenyl) 2572,5-diF-phenyl 2-(3-pyrrolidinylcarbonyl) 258 2,5-diF-phenyl 2-glycinoyl259 2,5-diF-phenyl 2-(imidazol-1-ylacetyl)

TABLE 3 a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

dd

ee

ff

gg

hh

ii

jj

kk

ll

mm

nn

oo

pp

qq

rr

Ex # A B 1 phenyl 2-(aminosulfonyl)phenyl 2 phenyl2-(methylaminosulfonyl)phenyl 3 phenyl 1-pyrrolidinocarbonyl 4 phenyl2-(methylsulfonyl)phenyl 5 phenyl 4-morpholino 6 phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 7 phenyl 4-morpholinocarbonyl 8 2-pyridyl2-(aminosulfonyl)phenyl 9 2-pyridyl 2-(methylaminosulfonyl)phenyl 102-pyridyl 1-pyrrolidinocarbonyl 11 2-pyridyl 2-(methylsulfonyl)phenyl 122-pyridyl 4-morpholino 13 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 142-pyridyl 4-morpholinocarbonyl 15 3-pyridyl 2-(aminosulfonyl)phenyl 163-pyridyl 2-(methylaminosulfonyl)phenyl 17 3-pyridyl1-pyrrolidinocarbonyl 18 3-pyridyl 2-(methylsulfonyl)phenyl 19 3-pyridyl4-morpholino 20 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 21 3-pyridyl4-morpholinocarbonyl 22 2-pyrimidyl 2-(aminosulfonyl)phenyl 232-pyrimidyl 2-(methylaminosulfonyl)phenyl 24 2-pyrimidyl1-pyrrolidinocarbonyl 25 2-pyrimidyl 2-(methylsulfonyl)phenyl 262-pyrimidyl 4-morpholino 27 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl28 2-pyrimidyl 4-morpholinocarbonyl 29 5-pyrimidyl2-(aminosulfonyl)phenyl 30 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 315-pyrimidyl 1-pyrrolidinocarbonyl 32 5-pyrimidyl2-(methylsulfonyl)phenyl 33 5-pyrimidyl 4-morpholino 34 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 35 5-pyrimidyl 4-morpholinocarbonyl 362-Cl-phenyl 2-(aminosulfonyl)phenyl 37 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 38 2-Cl-phenyl 1-pyrrolidinocarbonyl 392-Cl-phenyl 2-(methylsulfonyl)phenyl 40 2-Cl-phenyl 4-morpholino 412-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 42 2-Cl-phenyl4-morpholinocarbonyl 43 2-F-phenyl 2-(aminosulfonyl)phenyl 44 2-F-phenyl2-(methylaminosulfonyl)phenyl 45 2-F-phenyl 1-pyrrolidinocarbonyl 462-F-phenyl 2-(methylsulfonyl)phenyl 47 2-F-phenyl 4-morpholino 482-F-pheriyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 49 2-F-phenyl4-morpholinocarbonyl 50 2,5-diF-phenyl 2-(aminosulfonyl)phenyl 512,5-diF-phenyl 2-(methylaminosulfonyl)phenyl 52 2,5-diF-phenyl1-pyrrolidinocarbonyl 53 2,5-diF-phenyl 2-(methylsulfonyl)phenyl 542,5-diF-phenyl 4-morpholino 55 2,5-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 56 2,5-diF-phenyl 4-morpholinocarbonyl 57phenyl 2-(N-pyrrolidinyl-methyl)phenyl 58 phenyl2-(N-piperidinyl-methyl)phenyl 59 phenyl 2-(N-morpholino-methyl)phenyl60 phenyl 2-(N,N′-methylmorpholinium-methyl)phenyl 61 phenyl2-(N-pyridinium-methyl)phenyl 62 phenyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 63 phenyl2-(N-azatanyl-methyl)phenyl 64 phenyl 2-(N-azetidinyl-methyl)phenyl 65phenyl 2-(N-piperazinyl-methyl)phenyl 66 phenyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 67 phenyl2-(N-imidazolyl-methyl)phenyl 68 phenyl2-(N-methoxy-N-methylamino-methyl)phenyl 69 phenyl2-(N-pyridonyl-methyl)phenyl 70 phenyl2-(N-(N,N′-dimethylhydrazinyl-methyl)phenyl 71 phenyl 2-(amidinyl)phenyl72 phenyl 2-(N-guanidinyl)phenyl 73 phenyl 2-(imidazolyl)phenyl 74phenyl 2-(imidazolidinyl)phenyl 75 phenyl2-(2-imidazolidinyl-sulfonyl)phenyl 76 phenyl 2-(2-pyrrolidinyl)phenyl77 phenyl 2-(2-piperidinyl)phenyl 78 phenyl 2-(amidinyl-methyl)phenyl 79phenyl 2-(2-imidazolidinyl-methyl)phenyl 80 phenyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 81 phenyl2-dimethylaminoimidazol-1-yl 82 phenyl 2-(3-aminophenyl) 83 phenyl2-(3-pyrrolidinylcarbonyl) 84 phenyl 2-glycinoyl 85 phenyl2-(imidazol-1-ylacetyl) 86 2-pyridyl 2-(N-pyrrolidinyl-methyl)phenyl 872-pyridyl 2-(N-piperidinyl-methyl)phenyl 88 2-pyridyl2-(N-morpholino-methyl)phenyl 89 2-pyridyl2-(N,N′-methylmorpholinium-methyl)phenyl 90 2-pyridyl2-(N-pyridinium-methyl)phenyl 91 2-pyridyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 92 2-pyridyl2-(N-azatanyl-methyl)phenyl 93 2-pyridyl 2-(N-azetidinyl-methyl)phenyl94 2-pyridyl 2-(N-piperazinyl-methyl)phenyl 95 2-pyridyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 96 2-pyridyl2-(N-imidazolyl-methyl)phenyl 97 2-pyridyl2-(N-methoxy-N-methylamino-methyl)phenyl 98 2-pyridyl2-(N-pyridonyl-methyl)phenyl 99 2-pyridyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 100 2-pyridyl2-(amidinyl)phenyl 101 2-pyridyl 2-(N-guanidinyl)phenyl 102 2-pyridyl2-(imidazolyl)phenyl 103 2-pyridyl 2-(imidazolidinyl)phenyl 1042-pyridyl 2-(2-imidazolidinyl-sulfonyl)phenyl 105 2-pyridyl2-(2-pyrrolidinyl)phenyl 106 2-pyridyl 2-(2-piperidinyl)phenyl 1072-pyridyl 2-(amidinyl-methyl)phenyl 108 2-pyridyl2-(2-imidazolidinyl-methyl)phenyl 109 2-pyridyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 110 2-pyridyl2-dimethylaminoimidazol-1-yl 111 2-pyridyl 2-(3-aminophenyl) 1122-pyridyl 2-(3-pyrrolidinylcarbonyl) 113 2-pyridyl 2-glycinoyl 1142-pyridyl 2-(imidazol-1-ylacetyl) 115 3-pyridyl2-(N-pyrrolidinyl-methyl)phenyl 116 3-pyridyl2-(N-piperidinyl-methyl)phenyl 117 3-pyridyl2-(N-morpholino-methyl)phenyl 118 3-pyridyl2-(N,N′-methylmorpholinium-methyl)phenyl 119 3-pyridyl2-(N-pyridinium-methyl)phenyl 120 3-pyridyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 121 3-pyridyl2-(N-azatanyl-methyl)phenyl 122 3-pyridyl 2-(N-azetidinyl-methyl)phenyl123 3-pyridyl 2-(N-piperazinyl-methyl)phenyl 124 3-pyridyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 125 3-pyridyl2-(N-imidazolyl-methyl)phenyl 126 3-pyridyl2-(N-methoxy-N-methylamino-methyl)phenyl 127 3-pyridyl2-(N-pyridonyl-methyl)phenyl 128 3-pyridyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 129 3-pyridyl2-(amidinyl)phenyl 130 3-pyridyl 2-(N-guanidinyl)phenyl 131 3-pyridyl2-(imidazolyl)phenyl 132 3-pyridyl 2-(imidazolidinyl)phenyl 1333-pyridyl 2-(2-imidazolidinyl-sulfonyl)phenyl 134 3-pyridyl2-(2-pyrrolidinyl)phenyl 135 3-pyridyl 2-(2-piperidinyl)phenyl 1363-pyridyl 2-(amidinyl-methyl)phenyl 137 3-pyridyl2-(2-imidazolidinyl-methyl)phenyl 138 3-pyridyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 139 3-pyridyl2-dimethylaminoimidazol-1-yl 140 3-pyridyl 2-(3-aminophenyl) 1413-pyridyl 2-(3-pyrrolidinylcarbonyl) 142 3-pyridyl 2-glycinoyl 1433-pyridyl 2-(imidazol-1-ylacetyl) 144 2-pyrimidyl2-(N-pyrrolidinyl-methyl)phenyl 145 2-pyrimidyl2-(N-piperidinyl-methyl)phenyl 146 2-pyrimidyl2-(N-morpholino-methyl)phenyl 147 2-pyrimidyl2-(N,N′-methylmorpholinium-methyl)phenyl 148 2-pyrimidyl2-(N-pyridinium-methyl)phenyl 149 2-pyrimidyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 150 2-pyrimidyl2-(N-azatanyl-methyl)phenyl 151 2-pyrimidyl2-(N-azetidinyl-methyl)phenyl 152 2-pyrimidyl2-(N-piperazinyl-methyl)phenyl 153 2-pyrimidyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 154 2-pyrimidyl2-(N-imidazolyl-methyl)phenyl 155 2-pyrimidyl2-(N-methoxy-N-methylamino-methyl)phenyl 156 2-pyrimidyl2-(N-pyridonyl-methyl)phenyl 157 2-pyrimidyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 158 2-pyrimidyl2-(amidinyl)phenyl 159 2-pyrimidyl 2-(N-guanidinyl)phenyl 1602-pyrimidyl 2-(imidazolyl)phenyl 161 2-pyrimidyl2-(imidazolidinyl)phenyl 162 2-pyrimidyl2-(2-imidazolidinyl-sulfonyl)phenyl 163 2-pyrimidyl2-(2-pyrrolidinyl)phenyl 164 2-pyrimidyl 2-(2-piperidinyl)phenyl 1652-pyrimidyl 2-(amidinyl-methyl)phenyl 166 2-pyrimidyl2-(2-imidazolidinyl-methyl)phenyl 167 2-pyrimidyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 168 2-pyrimidyl2-dimethylaminoimidazol-1-yl 169 2-pyrimidyl 2-(3-aminophenyl) 1702-pyrimidyl 2-(3-pyrrolidinylcarbonyl) 171 2-pyrimidyl 2-glycinoyl 1722-pyrimidyl 2-(imidazol-1-ylacetyl) 173 2-Cl-phenyl2-(N-pyrrolidinyl-methyl)phenyl 174 2-Cl-phenyl2-(N-piperidinyl-methyl)phenyl 175 2-Cl-phenyl2-(N-morpholino-methyl)phenyl 176 2-Cl-phenyl2-(N,N′-methylmorpholinium-methyl)phenyl 177 2-Cl-phenyl2-(N-pyridinium-methyl)phenyl 178 2-Cl-phenyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 179 2-Cl-phenyl2-(N-azatanyl-methyl)phenyl 180 2-Cl-phenyl2-(N-azetidinyl-methyl)phenyl 181 2-Cl-phenyl2-(N-piperazinyl-methyl)phenyl 182 2-Cl-phenyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 183 2-Cl-phenyl2-(N-imidazolyl-methyl)phenyl 184 2-Cl-phenyl2-(N-methoxy-N-methylamino-methyl)phenyl 185 2-Cl-phenyl2-(N-pyridonyl-methyl) phenyl 186 2-Cl-phenyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 187 2-Cl-phenyl2-(amidinyl)phenyl 188 2-Cl-phenyl 2-(N-guanidinyl)phenyl 1892-Cl-phenyl 2-(imidazolyl)phenyl 190 2-Cl-phenyl2-(imidazolidinyl)phenyl 191 2-Cl-phenyl2-(2-imidazolidinyl-sulfonyl)phenyl 192 2-Cl-phenyl2-(2-pyrrolidinyl)phenyl 193 2-Cl-phenyl 2-(2-piperidinyl)phenyl 1942-Cl-phenyl 2-(amidinyl-methyl)phenyl 195 2-Cl-phenyl2-(2-imidazolidinyl-methyl)phenyl 196 2-Cl-phenyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 197 2-Cl-phenyl2-dimethylaminoimidazol-1-yl 198 2-Cl-phenyl 2-(3-aminophenyl) 1992-Cl-phenyl 2-(3-pyrrolidinylcarbonyl) 200 2-Cl-phenyl 2-glycinoyl 2012-Cl-phenyl 2-(imidazol-1-ylacetyl) 202 2-F-phenyl2-(N-pyrrolidinyl-methyl)phenyl 203 2-F-phenyl2-(N-piperidinyl-methyl)phenyl 204 2-F-phenyl2-(N-morpholino-methyl)phenyl 205 2-F-phenyl2-(N,N′-methylmorpholinium-methyl)phenyl 206 2-F-phenyl2-(N-pyridinium-methyl)phenyl 207 2-F-phenyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 208 2-F-phenyl2-(N-azatanyl-methyl)phenyl 209 2-F-phenyl 2-(N-azetidinyl-methyl)phenyl210 2-F-phenyl 2-(N-piperazinyl-methyl)phenyl 211 2-F-phenyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 212 2-F-phenyl2-(N-imidazolyl-methyl)phenyl 213 2-F-phenyl2-(N-methoxy-N-methylamino-methyl)phenyl 214 2-F-phenyl2-(N-pyridonyl-methyl)phenyl 215 2-F-phenyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 216 2-F-phenyl2-(amidinyl)phenyl 217 2-F-phenyl 2-(N-guanidinyl)phenyl 218 2-F-phenyl2-(imidazolyl)phenyl 219 2-F-phenyl 2-(imidazolidinyl)phenyl 2202-F-phenyl 2-(2-imidazolidinyl-sulfonyl)phenyl 221 2-F-phenyl2-(2-pyrrolidinyl)phenyl 222 2-F-phenyl 2-(2-piperidinyl)phenyl 2232-F-phenyl 2-(amidinyl-methyl)phenyl 224 2-F-phenyl2-(2-imidazolidinyl-methyl)phenyl 225 2-F-phenyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 226 2-F-phenyl2-dimethylaminoimidazol-1-yl 227 2-F-phenyl 2-(3-aminophenyl) 2282-F-phenyl 2-(3-pyrrolidinylcarbonyl) 229 2-F-phenyl 2-glycinoyl 2302-F-phenyl 2- (imidazol-1-ylacetyl) 231 2,5-diF-phenyl2-(N-pyrrolidinyl-methyl)phenyl 232 2,5-diF-phenyl2-(N-piperidinyl-methyl)phenyl 233 2,5-diF-phenyl2-(N-morpholino-methyl)phenyl 234 2,5-diF-phenyl2-(N,N′-methylmorpholinium-methyl)phenyl 235 2,5-diF-phenyl2-(N-pyridinium-methyl)phenyl 236 2,5-diF-phenyl2-(N-4-(N,N′-dimethylamino)-pyridinium-methyl) phenyl 237 2,5-diF-phenyl2-(N-azatanyl-methyl)phenyl 238 2,5-diF-phenyl2-(N-azetidinyl-methyl)phenyl 239 2,5-diF-phenyl2-(N-piperazinyl-methyl)phenyl 240 2,5-diF-phenyl2-(N,N′-BOC-piperazinyl-methyl)phenyl 241 2,5-diF-phenyl2-(N-imidazolyl-methyl)phenyl 242 2,5-diF-phenyl2-(N-methoxy-N-methylamino-methyl)phenyl 243 2,5-diF-phenyl2-(N-pyridonyl-methyl)phenyl 244 2,5-diF-phenyl2-(N-(N′,N′-dimethylhydrazinyl-methyl)phenyl 245 2,5-diF-phenyl2-(amidinyl)phenyl 246 2,5-diF-phenyl 2-(N-guanidinyl)phenyl 2472,5-diF-phenyl 2-(imidazolyl)phenyl 248 2,5-diF-phenyl2-(imidazolidinyl)phenyl 249 2,5-diF-phenyl2-(2-imidazolidinyl-sulfonyl)phenyl 250 2,5-diF-phenyl2-(2-pyrrolidinyl)phenyl 251 2,5-diF-phenyl 2-(2-piperidinyl)phenyl 2522,5-diF-phenyl 2-(amidinyl-methyl)phenyl 253 2,5-diF-phenyl2-(2-imidazolidinyl-methyl)phenyl 254 2,5-diF-phenyl2-(N-(2-aminoimidazolyl)-methyl)phenyl 255 2,5-diF-phenyl2-dimethylaminoimidazol-1-yl 256 2,5-diF-phenyl 2-(3-aminophenyl) 2572,5-diF-phenyl 2-(3-pyrrolidinylcarbonyl) 258 2,5-diF-phenyl 2-glycinoyl259 2,5-diF-phenyl 2-(imidazol-1-ylacetyl)

TABLE 4

a₁ R^(1a) = CH₃ a₂ R^(1a) = CF₃ a₃ R^(1a) = SCH₃ a₄ R^(1a) = SOCH₃ a₅R^(1a) = SO₂CH₃ a₆ R^(1a) = Cl a₇ R^(1a) = Br a₈ R^(1a) = CO₂CH₃ a₉R^(1a) = CH₂OCH₃

b₁ R^(1a) = CH₃ b₂ R^(1a) = CF₃ b₃ R^(1a) = SCH₃ b₄ R^(1a) = SOCH₃ b₅R^(1a) = SO₂CH₃ b₆ R^(1a) = Cl b₇ R^(1a) = Br b₈ R^(1a) = CO₂CH₃ b₉R^(1a) = CH₂OCH₃

c₁ R^(1a) = CH₃ c₂ R^(1a) = CF₃ c₃ R^(1a) = SCH₃ c₄ R^(1a) = SOCH₃ c₅R^(1a) = SO₂CH₃ c₆ R^(1a) = Cl c₇ R^(1a) = Br c₈ R^(1a) = CO₂CH₃ c₉R^(1a) = CH₂OCH₃

d₁ R^(1a) = CH₃ d₂ R^(1a) = CF₃ d₃ R^(1a) = SCH₃ d₄ R^(1a) = SOCH₃ d₅R^(1a) = SO₂CH₃ d₆ R^(1a) = Cl d₇ R^(1a) = Br d₈ R^(1a) = CO₂CH₃ d₉R^(1a) = CH₂OCH₃

e₁ R^(1a) = CH₃ e₂ R^(1a) = CF₃ e₃ R^(1a) = SCH₃ e₄ R^(1a) = SOCH₃ e₅R^(1a) = SO₂CH₃ e₆ R^(1a) = Cl e₇ R^(1a) = Br e₈ R^(1a) = CO₂CH₃ e₉R^(1a) = CH₂OCH₃

f₁ R^(1a) = CH₃ f₂ R^(1a) = CF₃ f₃ R^(1a) = SCH₃ f₄ R^(1a) = SOCH₃ f₅R^(1a) = SO₂CH₃ f₆ R^(1a) = Cl f₇ R^(1a) = Br f₈ R^(1a) = CO₂CH₃ f₉R^(1a) = CH₂OCH₃

g₁ R^(1a) = CH₃ g₂ R^(1a) = CF₃ g₃ R^(1a) = SCH₃ g₄ R^(1a) = SOCH₃ g₅R^(1a) = SO₂CH₃ g₆ R^(1a) = Cl g₇ R^(1a) = Br g₈ R^(1a) = CO₂CH₃ g₉R^(1a) = CH₂OCH₃

h₁ R^(1a) = CH₃ h₂ R^(1a) = CF₃ h₃ R^(1a) = SCH₃ h₄ R^(1a) = SOCH₃ h₅R^(1a) = SO₂CH₃ h₆ R^(1a) = Cl h₇ R^(1a) = Br h₈ R^(1a) = CO₂CH₃ h₉R^(1a) = CH₂OCH₃

i₁ R^(1a) = CH₃ i₂ R^(1a) = CF₃ i₃ R^(1a) = SCH₃ i₄ R^(1a) = SOCH₃ i₅R^(1a) = SO₂CH₃ i₆ R^(1a) = Cl i₇ R^(1a) = Br i₈ R^(1a) = CO₂CH₃ i₉R^(1a) = CH₂OCH₃

j₁ R^(1a) = CH₃ j₂ R^(1a) = CF₃ j₃ R^(1a) = SCH₃ j₄ R^(1a) = SOCH₃ j₅R^(1a) = SO₂CH₃ j₆ R^(1a) = Cl j₇ R^(1a) = Br j₈ R^(1a) = CO₂CH₃ j₉R^(1a) = CH₂OCH₃

k₁ R^(1a) = CH₃ k₂ R^(1a) = CF₃ k₃ R^(1a) = SCH₃ k₄ R^(1a) = SOCH₃ k₅R^(1a) = SO₂CH₃ k₆ R^(1a) = Cl k₇ R^(1a) = Br k₈ R^(1a) = CO₂CH₃ k₉R^(1a) = CH₂OCH₃

l₁ R^(1a) = CH₃ l₂ R^(1a) = CF₃ l₃ R^(1a) = SCH₃ l₄ R^(1a) = SOCH₃ l₅R^(1a) = SO₂CH₃ l₆ R^(1a) = Cl l₇ R^(1a) = Br l₈ R^(1a) = CO₂CH₃ l₉R^(1a) = CH₂OCH₃

m₁ R^(1a) = CH₃ m₂ R^(1a) = CF₃ m₃ R^(1a) = SCH₃ m₄ R^(1a) = SOCH₃ m₅R^(1a) = SO₂CH₃ m₆ R^(1a) = Cl m₇ R^(1a) = Br m₈ R^(1a) = CO₂CH₃ m₉R^(1a) = CH₂OCH₃

n₁ R^(1a) = CH₃ n₂ R^(1a) = CF₃ n₃ R^(1a) = SCH₃ n₄ R^(1a) = SOCH₃ n₅R^(1a) = SO₂CH₃ n₆ R^(1a) = Cl n₇ R^(1a) = Br n₈ R^(1a) = CO₂CH₃ n₉R^(1a) = CH₂OCH₃

o₁ R^(1a) = CH₃ o₂ R^(1a) = CF₃ o₃ R^(1a) = SCH₃ o₄ R^(1a) = SOCH₃ o₅R^(1a) = SO₂CH₃ o₆ R^(1a) = Cl o₇ R^(1a) = Br o₈ R^(1a) = CO₂CH₃ o₉R^(1a) = CH₂OCH₃

p₁ R^(1a) = CH₃ p₂ R^(1a) = CF₃ p₃ R^(1a) = SCH₃ p₄ R^(1a) = SOCH₃ p₅R^(1a) = SO₂CH₃ p₆ R^(1a) = Cl p₇ R^(1a) = Br p₈ R^(1a) = CO₂CH₃ p₉R^(1a) = CH₂OCH₃

q₁ R^(1a) = CH₃ q₂ R^(1a) = CF₃ q₃ R^(1a) = SCH₃ q₄ R^(1a) = SOCH₃ q₅R^(1a) = SO₂CH₃ q₆ R^(1a) = Cl q₇ R^(1a) = Br q₈ R^(1a) = CO₂CH₃ q₉R^(1a) = CH₂OCH₃

r₁ R^(1a) = CH₃ r₂ R^(1a) = CF₃ r₃ R^(1a) = SCH₃ r₄ R^(1a) = SOCH₃ r₅R^(1a) = SO₂CH₃ r₆ R^(1a) = Cl r₇ R^(1a) = Br r₈ R^(1a) = CO₂CH₃ r₉R^(1a) = CH₂OCH₃

s₁ R^(1a) = CH₃ s₂ R^(1a) = CF₃ s₃ R^(1a) = SCH₃ s₄ R^(1a) = SOCH₃ s₅R^(1a) = SO₂CH₃ s₆ R^(1a) = Cl s₇ R^(1a) = Br s₈ R^(1a) = CO₂CH₃ s₉R^(1a) = CH₂OCH₃

t₁ R^(1a) = CH₃ t₂ R^(1a) = CF₃ t₃ R^(1a) = SCH₃ t₄ R^(1a) = SOCH₃ t₅R^(1a) = SO₂CH₃ t₆ R^(1a) = Cl t₇ R^(1a) = Br t₈ R^(1a) = CO₂CH₃ t₉R^(1a) = CH₂OCH₃

u₁ R^(1a) = CH₃ u₂ R^(1a) = CF₃ u₃ R^(1a) = SCH₃ u₄ R^(1a) = SOCH₃ u₅R^(1a) = SO₂CH₃ u₆ R^(1a) = Cl u₇ R^(1a) = Br u₈ R^(1a) = CO₂CH₃ u₉R^(1a) = CH₂OCH₃

v₁ R^(1a) = CH₃ v₂ R^(1a) = CF₃ v₃ R^(1a) = SCH₃ v₄ R^(1a) = SOCH₃ v₅R^(1a) = SO₂CH₃ v₆ R^(1a) = Cl v₇ R^(1a) = Br v₈ R^(1a) = CO₂CH₃ v₉R^(1a) = CH₂OCH₃

w₁ R^(1a) = CH₃ w₂ R^(1a) = CF₃ w₃ R^(1a) = SCH₃ w₄ R^(1a) = SOCH₃ w₅R^(1a) = SO₂CH₃ w₆ R^(1a) = Cl w₇ R^(1a) = Br w₈ R^(1a) = CO₂CH₃ w₉R^(1a) = CH₂OCH₃

x₁ R^(1a) = CH₃ x₂ R^(1a) = CF₃ x₃ R^(1a) = SCH₃ x₄ R^(1a) = SOCH₃ x₅R^(1a) = SO₂CH₃ x₆ R^(1a) = Cl x₇ R^(1a) = Br x₈ R^(1a) = CO₂CH₃ x₉R^(1a) = CH₂OCH₃

y₁ R^(1a) = CH₃ y₂ R^(1a) = CF₃ y₃ R^(1a) = SCH₃ y₄ R^(1a) = SOCH₃ y₅R^(1a) = SO₂CH₃ y₆ R^(1a) = Cl y₇ R^(1a) = Br y₈ R^(1a) = CO₂CH₃ y₉R^(1a) = CH₂OCH₃ Ex # A B 1 phenyl 2-((Me)₂N-methyl)phenyl 2 phenyl2-((Me)NH-methyl)phenyl 3 phenyl 2-(H₂N-methyl)phenyl 4 phenyl2-HOCH₂-phenyl 5 2-F-phenyl 2-((Me)₂N-methyl)phenyl 6 2-F-phenyl2-((Me)NH-methyl)phenyl 7 2-F-phenyl 2-(H₂N-methyl)phenyl 8 2-F-phenyl2-HOCH₂-phenyl 9 phenyl 2-methylimidazol-1-yl 10 phenyl2-ethylimidazol-1-yl 11 phenyl 2-((Me)₂N-methyl)imidazol-1-yl 12 phenyl2-CH₃SO₂-imidazol-1-yl 13 phenyl 2-CH₃OCH₂-imidazol-1-yl 14 2-F-phenyl2-methylimidazol-1-yl 15 2-F-phenyl 2-ethylimidazol-1-yl 16 2-F-phenyl2-((Me)₂N-methyl)imidazol-1-yl 17 2-F-phenyl 2-CH₃SO₂-imidazol-1-yl 182-F-phenyl 2-CH₃OCH₂-imidazol-1-yl 19 2-Cl-phenyl 2-methylimidazol-1-yl20 2-Cl-phenyl 2-ethylimidlazol-1-yl 21 2-Cl-phenyl2-((Me)₂N-methyl)imidazol-1-yl 22 2-Cl-phenyl 2-CH₃SO₂-imidazol-1-yl 232-Cl-phenyl 2-CH₃OCH₂-imidazol-1-yl 24 2-(Me)₂N-phenyl2-methylimidazol-1-yl 25 2-(Ne)₂N-phenyl 2-ethylimidazol-1-yl 262-(Me)₂N-phenyl 2-((Me)₂N-methyl)imidazol-1-yl 27 2-(Me)₂N-phenyl2-CH₃SO₂-imidazol-1-yl 28 2-(Me)₂N-phenyl 2-CH₃OCH₂-imidazol-1-yl 29phenyl N-methylimidazol-2-yl 30 phenyl 4-methylimidazol-5-yl 31 phenyl5-CF₃-pyrazol-1-yl 32 2-F-phenyl N-methylimidazol-2-yl 33 2-F-phenyl4-methylimidazol-5-yl 34 2-F-phenyl 5-CF₃-pyrazol-1-yl 35 phenylguanidino 36 phenyl 2-thiazolin-2-ylamine 37 phenylN-methyl-2-imidazolin-2-yl 38 phenylN-methyl-1,4,5,6-tetrahydropyrimid-2-yl 39 phenylN-methylimidazol-2-ylthiol 40 phenyl t-butoxycarbonylamine 41 phenyl(N-pyrrolidino)formylimino 42 phenyl(N-pyrrolidino)formyl-N-methanesulfamoyl) imino 43 2-F-phenyl guanidino44 2-F-phenyl 2-thiazolin-2-ylamine 45 2-F-phenylN-methyl-2-imidazolin-2-yl 46 2-F-phenylN-methyl-1,4,5,6-tetrahydropyrimid-2-yl 47 2-F-phenylN-methylimidazol-2-ylthio 48 2-F-phenyl t-butoxycarbonylamine 492-F-phenyl (N-pyrrolidino)formylimino 50 2-F-phenyl(N-pyrrolidino)formyl-N-methanesulfamoyl) imino 51 2-CH₃O-phenyl(N-pyrrolidino)formylimino 52 2-CH₃O-phenyl(N-pyrrolidino)formyl-N-(methanesulfamoyl) imino

TABLE 5 a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

dd

ee

ff

gg

hh

ii

jj

kk

ll

mm

nn

oo

pp

qq

rr

Ex # A B 1 phenyl 2-((Me)₂N-methyl)phenyl 2 phenyl2-((Me)NH-methyl)phenyl 3 phenyl 2-(H₂N-methyl)phenyl 4 phenyl2-HOCH₂-phenyl 5 2-F-phenyl 2-((Me)₂N-methyl)phenyl 6 2-F-phenyl2-((Me)NH-methyl)phenyl 7 2-F-phenyl 2-(H₂N-methyl)phenyl 8 2-F-phenyl2-HOCH₂-phenyl 9 phenyl 2-methylimidazol-1-yl 10 phenyl2-ethylimidazol-1-yl 11 phenyl 2-((Me)₂N-methyl)imidazol-1-yl 12 phenyl2-CH₃SO₂-imidazol-1-yl 13 phenyl 2-CH₃OCH₂-imidazol-1-yl 14 2-F-phenyl2-methylimidazol-1-yl 15 2-F-phenyl 2-ethylimidazol--1-yl 16 2-F-phenyl2-((Me)₂N-methyl)imidazol-1-yl 17 2-F-phenyl 2-CH₃SO₂-imidazol-1-yl 182-F-phenyl 2-CH₃OCH₂-imidazol-1-yl 19 2-Cl-phenyl 2-methylimidazol-1-yl20 2-Cl-phenyl 2-ethylimidazol-1-yl 21 2-Cl-phenyl2-((Me)₂N-methyl)imidazol-1-yl 22 2-Cl-phenyl 2-CH₃SO₂-imidazol-1-yl 232-Cl-phenyl 2-CH₃OCH₂-imidazol-1-yl 24 2-(Me)₂N-phenyl2-methylimiclazol-1-yl 25 2-(Me)₂N-phenyl 2-ethylimidazol-1-yl 262-(Me)₂N-phenyl 2-((Me)₂N-methyl)imidazol-1-yl 27 2-(Me)₂N-phenyl2-CH₃SO₂-imidazol-1-yl 28 2-(Me)₂N-phenyl 2-CH₃OCH₂-imidazol-1-yl 29phenyl N-methylimidazol-2-yl 30 phenyl 4-methylimidazol-5-yl 31 phenyl5-CF₃-pyrazol-1-yl 32 2-F-phenyl N-methylimidazol-2-yl 33 2-F-phenyl4-methylimidazol-5-yl 34 2-F-phenyl 5-CF₃-pyrazol-1-yl 35 phenylguanidino 36 phenyl 2-thiazolin-2-ylamine 37 phenylN-methyl-2-imidazolin-2-yl 38 phenylN-methyl-1,4,5,6-tetrahydropyrimid-2-yl 39 phenylN-methylimidazol-2-ylthiol 40 phenyl t-butoxycarbonylamine 41 phenyl(N-pyrrolidino)formylimino 42 phenyl(N-pyrrolidino)formyl-N-methanesulfamoyl) imino 43 2-F-phenyl guanidino44 2-F-phenyl 2-thiazolin-2-ylamine 45 2-F-phenylN-methyl-2-imidazolin-2-yl 46 2-F-phenylN-methyl-1,4,5,6-tetrahydropyrimid-2-yl 47 2-F-phenylN-methylimidazol-2-ylthio 48 2-F-phenyl t-butoxycarbonylamine 492-F-phenyl (N-pyrrolidino)formylimino 50 2-F-phenyl(N-pyrrolidino)formyl-N-methanesulfamoyl) imino 51 2-CH₃O-phenyl(N-pyrrolidino)formylimino 52 2-CH₃O-phenyl(N-pyrrolidino)formyl-N-(methanesulfamoyl) imino

TABLE 6 a

b

c₁ R⁴ = OCH₃ c₂ R⁴ = CO₂CH₃ c₃ R⁴ = CH₂OCH₃ c₄ R⁴ = CH₃ c₅ R⁴ = CF₃ c₆R⁴ = Cl c₇ R⁴ = F

d₁ R⁴ = OCH₃ d₂ R⁴ = CO₂CH₃ d₃ R⁴ = CH₂OCH₃ d₄ R⁴ = CH₃ d₅ R⁴ = CF₃ d₆R⁴ = Cl d₇ R⁴ = F

e₁ R⁴ = OCH₃ e₂ R⁴ = CO₂CH₃ e₃ R⁴ = CH₂OCH₃ e₄ R⁴ = CH₃ e₅ R⁴ = CF₃ e₆R⁴ = Cl e₇ R⁴ = F

f₁ R⁴ = OCH₃ f₂ R⁴ = CO₂CH₃ f₃ R⁴ = CH₂OCH₃ f₄ R⁴ = CH₃ f₅ R⁴ = CF₃ f₆R⁴ = Cl f₇ R⁴ = F

g₁ R⁴ = OCH₃ g₂ R⁴ = CO₂CH₃ g₃ R⁴ = CH₂OCH₃ g₄ R⁴ = CH₃ g₅ R⁴ = CF₃ g₆R⁴ = Cl g₇ R⁴ = F

h₁ R⁴ = OCH₃ h₂ R⁴ = CO₂CH₃ h₃ R⁴ = CH₂OCH₃ h₄ R⁴ = CH₃ h₅ R⁴ = CF₃ h₆R⁴ = Cl h₇ R⁴ = F

i₁ R⁴ = OCH₃ i₂ R⁴ = CO₂CH₃ i₃ R⁴ = CH₂OCH₃ i₄ R⁴ = CH₃ i₅ R⁴ = CF₃ i₆R⁴ = Cl i₇ R⁴ = F

j₁ R⁴ = OCH₃ j₂ R⁴ = CO₂CH₃ j₃ R⁴ = CH₂OCH₃ j₄ R⁴ = CH₃ j₅ R⁴ = CF₃ j₆R⁴ = Cl j₇ R⁴ = F k

l

m₁ R⁴ = OCH₃ m₂ R⁴ = CO₂CH₃ m₃ R⁴ = CH₂OCH₃ m₄ R⁴ = CH₃ m₅ R⁴ = CF₃ m₆R⁴ = Cl m₇ R⁴ = F

n₁ R⁴ = OCH₃ n₂ R⁴ = CO₂CH₃ n₃ R⁴ = CH₂OCH₃ n₄ R⁴ = CH₃ n₅ R⁴ = CF₃ n₆R⁴ = Cl n₇ R⁴ = F

o₁ R⁴ = OCH₃ o₂ R⁴ = CO₂CH₃ o₃ R⁴ = CH₂OCH₃ o₄ R⁴ = CH₃ o₅ R⁴ = CF₃ o₆R⁴ = Cl o₇ R⁴ = F

p₁ R⁴ = OCH₃ p₂ R⁴ = CO₂CH₃ p₃ R⁴ = CH₂OCH₃ p₄ R⁴ = CH₃ p₅ R⁴ = CF₃ p₆R⁴ = Cl p₇ R⁴ = F

q₁ R⁴ = OCH₃ q₂ R⁴ = CO₂CH₃ q₃ R⁴ = CH₂OCH₃ q₄ R⁴ = CH₃ q₅ R⁴ = CF₃ q₆R⁴ = Cl q₇ R⁴ = F

r₁ R⁴ = OCH₃ r₂ R⁴ = CO₂CH₃ r₃ R⁴ = CH₂OCH₃ r₄ R⁴ = CH₃ r₅ R⁴ = CF₃ r₆R⁴ = Cl r₇ R⁴ = F

s₁ R⁴ = OCH₃ s₂ R⁴ = CO₂CH₃ s₃ R⁴ = CH₂OCH₃ s₄ R⁴ = CH₃ s₅ R⁴ = CF₃ s₆R⁴ = Cl s₇ R⁴ = F

t₁ R⁴ = OCH₃ t₂ R⁴ = CO₂CH₃ t₃ R⁴ = CH₂OCH₃ t₄ R⁴ = CH₃ t₅ R⁴ = CF₃ t₆R⁴ = Cl t₇ R⁴ = F u

v

w₁ R⁴ = OCH₃ w₂ R⁴ = CO₂CH₃ w₃ R⁴ = CH₂OCH₃ w₄ R⁴ = CH₃ w₅ R⁴ = CF₃ w₆R⁴ = Cl w₇ R⁴ = F

x₁ R⁴ = OCH₃ x₂ R⁴ = CO₂CH₃ x₃ R⁴ = CH₂OCH₃ x₄ R⁴ = CH₃ x₅ R⁴ = CF₃ x₆R⁴ = Cl x₇ R⁴ = F

y₁ R⁴ = OCH₃ y₂ R⁴ = CO₂CH₃ y₃ R⁴ = CH₂OCH₃ y₄ R⁴ = CH₃ y₅ R⁴ = CF₃ y₆R⁴ = Cl y₇ R⁴ = F

z₁ R⁴ = OCH₃ z₂ R⁴ = CO₂CH₃ z₃ R⁴ = CH₂OCH₃ z₄ R⁴ = CH₃ z₅ R⁴ = CF₃ z₆R⁴ = Cl z₇ R⁴ = F

aa₁ R⁴ = OCH₃ aa₂ R⁴ = CO₂CH₃ aa₃ R⁴ = CH₂OCH₃ aa₄ R⁴ = CH₃ aa₅ R⁴ = CF₃aa₆ R⁴ = Cl aa₇ R⁴ = F

bb₁ R⁴ = OCH₃ bb₂ R⁴ = CO₂CH₃ bb₃ R⁴ = CH₂OCH₃ bb₄ R⁴ = CH₃ bb₅ R⁴ = CF₃bb₆ R⁴ = Cl bb₇ R⁴ = F

cc₁ R⁴ = OCH₃ cc₂ R⁴ = CO₂CH₃ cc₃ R⁴ = CH₂OCH₃ cc₄ R⁴ = CH₃ cc₅ R⁴ = CF₃cc₆ R⁴ = Cl cc₇ R⁴ = F

dd₁ R⁴ = OCH₃ dd₂ R⁴ = CO₂CH₃ dd₃ R⁴ = CH₂OCH₃ dd₄ R⁴ = CH₃ dd₅ R⁴ = CF₃dd₆ R⁴ = Cl dd₇ R⁴ = F Ex # A B 1 phenyl 2-(aminosulfonyl)phenyl 2phenyl 2-(methylaminosulfonyl)phenyl 3 phenyl 1-pyrrolidinocarbonyl 4phenyl 2-(methylsulfonyl)phenyl 5 phenyl 4-morpholino 6 phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 7 phenyl 4-morpholinocarbonyl 8 2-pyridyl2-(aminosulfonyl)phenyl 9 2-pyridyl 2-(methylaminosulfonyl)phenyl 102-pyridyl 1-pyrrolidinocarbonyl 11 2-pyridyl 2-(methylsulfonyl)phenyl 122-pyridyl 4-morpholino 13 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 142-pyridyl 4-morpholinocarbonyl 15 3-pyridyl 2-(aminosulfonyl)phenyl 163-pyridyl 2-(methylaminosulfonyl)phenyl 17 3-pyridyl1-pyrrolidinocarbonyl 18 3-pyridyl 2-(methylsulfonyl)phenyl 19 3-pyridyl4-morpholino 20 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 21 3-pyridyl4-morpholinocarbonyl 22 2-pyrimidyl 2-(aminosulfonyl)phenyl 232-pyrimidyl 2-(methylaminosulfonyl)phenyl 24 2-pyrimidyl1-pyrrolidinocarbonyl 25 2-pyrimidyl 2-(methylsulfonyl)phenyl 262-pyrimidyl 4-morpholino 27 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl28 2-pyrimidyl 4-morpholinocarbonyl 29 5-pyrimidyl2-(aminosulfonyl)phenyl 30 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 315-pyrimidyl 1-pyrrolidinocarbonyl 32 5-pyrimidyl2-(methylsulfonyl)phenyl 33 5-pyrimidyl 4-morpholino 34 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 35 5-pyrimidyl 4-morpholinocarbonyl 362-Cl-phenyl 2-(aminosulfonyl)phenyl 37 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 38 2-Cl-phenyl 1-pyrrolidinocarbonyl 392-Cl-phenyl 2-(methylsulfonyl)phenyl 40 2-Cl-phenyl 4-morpholino 412-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 42 2-Cl-phenyl4-morpholinocarbonyl 43 2-F-phenyl 2-(aminosulfonyl)phenyl 44 2-F-phenyl2-(methylaminosulfonyl)phenyl 45 2-F-phenyl 1-pyrrolidinocarbonyl 462-F-phenyl 2-(methylsulfonyl)phenyl 47 2-F-phenyl 4-morpholino 482-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 49 2-F-phenyl4-morpholinocarbonyl 50 2,5-diF-phenyl 2-(aminosulfonyl)phenyl 512,5-diF-phenyl 2-(methylaminosulfonyl)phenyl 52 2,5-diF-phenyl1-pyrrolidinocarbonyl 53 2,5-diF-phenyl 2-(methylsulfonyl)phenyl 542,5-diF-phenyl 4-morpholino 55 2,5-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 56 2,5-diF-phenyl 4-morpholinocarbonyl

TABLE 7 a

b

c₁ R⁴ = OCH₃ c₂ R⁴ = CO₂CH₃ c₃ R⁴ = CH₂OCH₃ c₄ R⁴ = CH₃ c₅ R⁴ = CF₃ c₆R⁴ = Cl c₇ R⁴ = F

d₁ R⁴ = OCH₃ d₂ R⁴ = CO₂CH₃ d₃ R⁴ = CH₂OCH₃ d₄ R⁴ = CH₃ d₅ R⁴ = CF₃ d₆R⁴ = Cl d₇ R⁴ = F

e₁ R⁴ = OCH₃ e₂ R⁴ = CO₂CH₃ e₃ R⁴ = CH₂OCH₃ e₄ R⁴ = CH₃ e₅ R⁴ = CF₃ e₆R⁴ = Cl e₇ R⁴ = F

f₁ R⁴ = OCH₃ f₂ R⁴ = CO₂CH₃ f₃ R⁴ = CH₂OCH₃ f₄ R⁴ = CH₃ f₅ R⁴ = CF₃ f₆R⁴ = Cl f₇ R⁴ = F

g₁ R⁴ = OCH₃ g₂ R⁴ = CO₂CH₃ g₃ R⁴ = CH₂OCH₃ g₄ R⁴ = CH₃ g₅ R⁴ = CF₃ g₆R⁴ = Cl g₇ R⁴ = F

h₁ R⁴ = OCH₃ h₂ R⁴ = CO₂CH₃ h₃ R⁴ = CH₂OCH₃ h₄ R⁴ = CH₃ h₅ R⁴ = CF₃ h₆R⁴ = Cl h₇ R⁴ = F

i₁ R⁴ = OCH₃ i₂ R⁴ = CO₂CH₃ i₃ R⁴ = CH₂OCH₃ i₄ R⁴ = CH₃ i₅ R⁴ = CF₃ i₆R⁴ = Cl i₇ R⁴ = F

j₁ R⁴ = OCH₃ j₂ R⁴ = CO₂CH₃ j₃ R⁴ = CH₂OCH₃ j₄ R⁴ = CH₃ j₅ R⁴ = CF₃ j₆R⁴ = Cl j₇ R⁴ = F k

l

m₁ R⁴ = OCH₃ m₂ R⁴ = CO₂CH₃ m₃ R⁴ = CH₂OCH₃ m₄ R⁴ = CH₃ m₅ R⁴ = CF₃ m₆R⁴ = Cl m₇ R⁴ = F

n₁ R⁴ = OCH₃ n₂ R⁴ = CO₂CH₃ n₃ R⁴ = CH₂OCH₃ n₄ R⁴ = CH₃ n₅ R⁴ = CF₃ n₆R⁴ = Cl n₇ R⁴ = F

o₁ R⁴ = OCH₃ o₂ R⁴ = CO₂CH₃ o₃ R⁴ = CH₂OCH₃ o₄ R⁴ = CH₃ o₅ R⁴ = CF₃ o₆R⁴ = Cl o₇ R⁴ = F

p₁ R⁴ = OCH₃ p₂ R⁴ = CO₂CH₃ p₃ R⁴ = CH₂OCH₃ p₄ R⁴ = CH₃ p₅ R⁴ = CF₃ p₆R⁴ = Cl p₇ R⁴ = F

q₁ R⁴ = OCH₃ q₂ R⁴ = CO₂CH₃ q₃ R⁴ = CH₂OCH₃ q₄ R⁴ = CH₃ q₅ R⁴ = CF₃ q₆R⁴ = Cl q₇ R⁴ = F

r₁ R⁴ = OCH₃ r₂ R⁴ = CO₂CH₃ r₃ R⁴ = CH₂OCH₃ r₄ R⁴ = CH₃ r₅ R⁴ = CF₃ r₆R⁴ = Cl r₇ R⁴ = F

s₁ R⁴ = OCH₃ s₂ R⁴ = CO₂CH₃ s₃ R⁴ = CH₂OCH₃ s₄ R⁴ = CH₃ s₅ R⁴ = CF₃ s₆R⁴ = Cl s₇ R⁴ = F

t₁ R⁴ = OCH₃ t₂ R⁴ = CO₂CH₃ t₃ R⁴ = CH₂OCH₃ t₄ R⁴ = CH₃ t₅ R⁴ = CF₃ t₆R⁴ = Cl t₇ R⁴ = F u

v

w₁ R⁴ = OCH₃ w₂ R⁴ = CO₂CH₃ w₃ R⁴ = CH₂OCH₃ w₄ R⁴ = CH₃ w₅ R⁴ = CF₃ w₆R⁴ = Cl w₇ R⁴ = F

x₁ R⁴ = OCH₃ x₂ R⁴ = CO₂CH₃ x₃ R⁴ = CH₂OCH₃ x₄ R⁴ = CH₃ x₅ R⁴ = CF₃ x₆R⁴ = Cl x₇ R⁴ = F

y₁ R⁴ = OCH₃ y₂ R⁴ = CO₂CH₃ y₃ R⁴ = CH₂OCH₃ y₄ R⁴ = CH₃ y₅ R⁴ = CF₃ y₆R⁴ = Cl y₇ R⁴ = F

z₁ R⁴ = OCH₃ z₂ R⁴ = CO₂CH₃ z₃ R⁴ = CH₂OCH₃ z₄ R⁴ = CH₃ z₅ R⁴ = CF₃ z₆R⁴ = Cl z₇ R⁴ = F

aa₁ R⁴ = OCH₃ aa₂ R⁴ = CO₂CH₃ aa₃ R⁴ = CH₂OCH₃ aa₄ R⁴ = CH₃ aa₅ R⁴ = CF₃aa₆ R⁴ = Cl aa₇ R⁴ = F

bb₁ R⁴ = OCH₃ bb₂ R⁴ = CO₂CH₃ bb₃ R⁴ = CH₂OCH₃ bb₄ R⁴ = CH₃ bb₅ R⁴ = CF₃bb₆ R⁴ = Cl bb₇ R⁴ = F

cc₁ R⁴ = OCH₃ cc₂ R⁴ = CO₂CH₃ cc₃ R⁴ = CH₂OCH₃ cc₄ R⁴ = CH₃ cc₅ R⁴ = CF₃cc₆ R⁴ = Cl cc₇ R⁴ = F

dd₁ R⁴ = OCH₃ dd₂ R⁴ = CO₂CH₃ dd₃ R⁴ = CH₂OCH₃ dd₄ R⁴ = CH₃ dd₅ R⁴ = CF₃dd₆ R⁴ = Cl dd₇ R⁴ = F Ex # A B 1 phenyl 2-((Me)₂N-methyl)phenyl 2phenyl 2-((Me)NH-methyl)phenyl 3 phenyl 2-(H₂N-methyl)phenyl 4 phenyl2-HOCH₂-phenyl 5 2-F-phenyl 2-((Me)₂N-methyl)phenyl 6 2-F-phenyl2-((Me)NH-methyl)phenyl 7 2-F-phenyl 2-(H₂N-methyl)phenyl 8 2-F-phenyl2-HOCH₂-phenyl 9 phenyl 2-methylimidazol-1-yl 10 phenyl2-ethylimidazol-1-yl 11 phenyl 2-((Me)₂N-methyl)imidazol-1-yl 12 phenyl2-CH₃SO₂-imidazol-1-yl 13 phenyl 2-CH₃OCH₂-imidazol-1-yl 14 2-F-phenyl2-methylimidazol-1-yl 15 2-F-phenyl 2-ethylimidazol-1-yl 16 2-F-phenyl2-((Me)₂N-methyl)imidazol-1-yl 17 2-F-phenyl 2-CH₃SO₂-imidazol-1-yl 182-F-phenyl 2-CH₃OCH₂-imidazol-1-yl 19 2-Cl-phenyl 2-methylimidazol-1-yl20 2-Cl-phenyl 2-ethylimidazol-1-yl 21 2-Cl-phenyl2-((Me)₂N-methyl)imidazol-1-yl 22 2-Cl-phenyl 2-CH₃SO₂-imidazol-1-yl 232-Cl-phenyl 2-CH₃OCH₂-imidazol-1-yl 24 2-(Me)₂N-phenyl2-methylimidazol-1-yl 25 2-(Me)₂N-phenyl 2-ethylimidazol-1-yl 262-(Me)₂N-phenyl 2-((Me)₂N-methyl)imidazol-1-yl 27 2-(Me)₂N-phenyl2-CH₃SO₂-imidazol-1-yl 28 2-(Me)₂N-phenyl 2-CH₃OCH₂-imidazol-1-yl 29phenyl N-methylimidazol-2-yl 30 phenyl 4-methylimidazol-5-yl 31 phenyl5-CF₃-pyrazol-1-yl 32 2-F-phenyl N-methylimidazol-2-yl 33 2-F-phenyl4-methylimidazol-5-yl 34 2-F-phenyl 5-CF₃-pyrazol-1-yl 35 phenylguanidino 36 phenyl 2-thiazolin-2-ylamine 37 phenylN-methyl-2-imidazolin-2-yl 38 phenylN-methyl-1,4,5,6-tetrahydropyrimid-2-yl 39 phenylN-methylimidazol-2-ylthiol 40 phenyl t-butoxycarbonylamine 41 phenyl(N-pyrrolidino)formylimino 42 phenyl(N-pyrrolidino)formyl-N-methanesulfamoyl) imino 43 2-F-phenyl guanidino44 2-F-phenyl 2-thiazolin-2-ylamine 45 2-F-phenylN-methyl-2-imidazolin-2-yl 46 2-F-phenylN-methyl-1,4,5,6-tetrahydropyrimid-2-yl 47 2-F-phenylN-methylimidazol-2-ylthio 48 2-F-phenyl t-butoxycarbonylamine 492-F-phenyl (N-pyrrolidino)formylimino 50 2-F-phenyl(N-pyrrolidino)formyl-N-methanesulfamoyl) imino 51 2-CH₃O-phenyl(N-pyrrolidino)formylimino 52 2-CH₃O-phenyl(N-pyrrolidino)formyl-N-(methanesulfamoyl) imino

Utility

The compounds of this invention are useful as anticoagulants for thetreatment or prevention of thromboembolic disorders in mammals. The term“thromboembolic disorders” as used herein includes arterial or venouscardiovascular or cerebrovascular thromboembolic disorders, including,for example, unstable angina, first or recurrent myocardial infarction,ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, cerebral embolism, kidney embolisms, and pulmonaryembolisms. The anticoagulant effect of compounds of the presentinvention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors offactor Xa was determined using purified human factor Xa and syntheticsubstrate. The rate of factor Xa hydrolysis of chromogenic substrateS2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absenceand presence of compounds of the present invention. Hydrolysis of thesubstrate resulted in the release of pNA, which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nM. A decrease in the rate of absorbance change at 405 nm in thepresence of inhibitor is indicative of enzyme inhibition. The results ofthis assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant,K_(m), for substrate hydrolysis was determined at 25° C. using themethod of Lineweaver and Burk. Values of K_(i) were determined byallowing 0.2–0.5 nM human factor Xa (Enzyme Research Laboratories, SouthBend, Ind.) to react with the substrate (0.20 mM−1 mM) in the presenceof inhibitor. Reactions were allowed to go for 30 minutes and thevelocities (rate of absorbance change vs time) were measured in the timeframe of 25–30 minutes. The following relationship was used to calculateK_(i) values:(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m)))where:

-   -   v_(o) is the velocity of the control in the absence of        inhibitor;    -   v_(s) is the velocity in the presence of inhibitor;    -   I is the concentration of inhibitor;    -   K_(i) is the dissociation constant of the enzyme:inhibitor        complex;    -   S is the concentration of substrate;    -   K_(m) is the Michaelis constant.        Using the methodology described above, a number of compounds of        the present invention were found to exhibit a K_(i) of ≦15 μM,        thereby confirming the utility of the compounds of the present        invention as effective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can bedemonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. Inthis model, rabbits weighing 2–3 kg anesthetized with a mixture ofxylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. Asaline-filled AV shunt device is connected between the femoral arterialand the femoral venous cannulae. The AV shunt device consists of a pieceof 6-cm tygon tubing which contains a piece of silk thread. Blood willflow from the femoral artery via the AV-shunt into the femoral vein. Theexposure of flowing blood to a silk thread will induce the formation ofa significant thrombus. After forty minutes, the shunt is disconnectedand the silk thread covered with thrombus is weighed. Test agents orvehicle will be given (i.v., i.p., s.c., or orally) prior to the openingof the AV shunt. The percentage inhibition of thrombus formation isdetermined for each treatment group. The ID50 values (dose whichproduces 50% inhibition of thrombus formation) are estimated by linearregression.

The compounds of formula (I) may also be useful as inhibitors of serineproteases, notably human thrombin, plasma kallikrein and plasmin.Because of their inhibitory action, these compounds are indicated foruse in the prevention or treatment of physiological reactions, bloodcoagulation and inflammation, catalyzed by the aforesaid class ofenzymes. Specifically, the compounds have utility as drugs for thetreatment of diseases arising from elevated thrombin activity such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

Some compounds of the present invention were shown to be direct actinginhibitors of the serine protease thrombin by their ability to inhibitthe cleavage of small molecule substrates by thrombin in a purifiedsystem. In vitro inhibition constants were determined by the methoddescribed by Kettner et al. in J. Biol. Chem. 265, 18289–18297 (1990),herein incorporated by reference. In these assays, thrombin-mediatedhydrolysis of the chromogenic substrate S2238 (Helena Laboratories,Beaumont, Tex.) was monitored spectrophotometrically. Addition of aninhibitor to the assay mixture results in decreased absorbance and isindicative of thrombin inhibition. Human thrombin (Enzyme ResearchLaboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000,was incubated with various substrate concentrations ranging from 0.20 to0.02 mM. After 25 to 30 minutes of incubation, thrombin activity wasassayed by monitoring the rate of increase in absorbance at 405 nm whicharises owing to substrate hydrolysis. Inhibition constants were derivedfrom reciprocal plots of the reaction velocity as a function ofsubstrate concentration using the standard method of Lineweaver andBurk. Using the methodology described above, some compounds of thisinvention were evaluated and found to exhibit a K_(i) of less than 15μm, thereby confirming the utility of the compounds of the presentinvention as effective Xa inhibitors.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. Theseinclude other anti-coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, thrombin inhibitors, orthrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

By “administered in combination” or “combination therapy” it is meantthat the compound of Formula I and one or more additional therapeuticagents are administered concurrently to the mammal being treated. Whenadministered in combination each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component may be administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect. Otheranticoagulant agents (or coagulation inhibitory agents) that may be usedin combination with the compounds of this invention include warfarin andheparin, as well as other factor Xa inhibitors such as those describedin the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include, but are not limited to, the various knownnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, and piroxicam, including pharmaceuticallyacceptable salts or prodrugs thereof. Of the NSAIDS, aspirin(acetylsalicyclic acid or ASA), and piroxicam are preferred. Othersuitable anti-platelet agents include ticlopidine, includingpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine isalso a preferred compound since it is known to be gentle on thegastro-intestinal tract in use. Still other suitable platelet inhibitoryagents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonistsand thromboxane-A2-synthetase inhibitors, as well as pharmaceuticallyacceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin and argatroban, includingpharmaceutically acceptable salts and prodrugs thereof. Boroargininederivatives and boropeptides include N-acetyl and peptide derivatives ofboronic acid, such as C-terminal a-aminoboronic acid derivatives oflysine, ornithine, arginine, homoarginine and correspondingisothiouronium analogs thereof. The term hirudin, as used herein,includes suitable derivatives or analogs of hirudin, referred to hereinas hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitorsinclude compounds described in Kettner et al., U.S. Pat. No. 5,187,157and European Patent Application Publication Number 293 881 A2, thedisclosures of which are hereby incorporated herein by reference. Othersuitable boroarginine derivatives and boropeptide thrombin inhibitorsinclude those disclosed in PCT Application Publication No. 92/07869 andEuropean Patent Application Publication Number 471,651 A2, thedisclosures of which are hereby incorporated herein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator,anistreplase, urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in European Patent Application No.028,489, the disclosure of which is hereby incorporated herein byreference herein. The term urokinase, as used herein, is intended todenote both dual and single chain urokinase, the latter also beingreferred to herein as prourokinase.

Administration of the compounds of Formula I of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of factor Xa. Such compoundsmay be provided in a commercial kit, for example, for use inpharmaceutical research involving factor Xa. For example, a compound ofthe present invention could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention couldbe used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving factor Xa. For example, the presence of factor Xa in anunknown sample could be determined by addition of chromogenic substrateS2222 to a series of solutions containing test sample and optionally oneof the compounds of the present invention. If production of pNA isobserved in the solutions containing test sample, but no compound of thepresent invention, then one would conclude factor Xa was present.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5–95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with ananti-platelet agent, by way of general guidance, typically a dailydosage may be about 0.01 to 25 milligrams of the compound of Formula Iand about 50 to 150 milligrams of the anti-platelet agent, preferablyabout 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are adminstered in combination withthrombolytic agent, typically a daily dosage may be about 0.1 to 1milligrams of the compound of Formula I, per kilogram of patient bodyweight and, in the case of the thrombolytic agents, the usual dosage ofthe thrombolyic agent when administered alone may be reduced by about70–80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;D-E is 3-aminobenzisoxazol-5-yl or 3-hydroxybenzisoxazol-5-yl; M is

Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r)O(CH₂)_(r),(CH₂)_(r)NR³(CH₂)_(r), (CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r)C(O)O(CH₂)_(r),(CH₂)_(r)OC(O)(CH₂)_(r), (CH₂)_(r)C(O)NR³(CH₂)_(r),(CH₂)_(r)NR³C(O)(CH₂)_(r), (CH₂)_(r)OC(O)O(CH₂)_(r),(CH₂)_(r)OC(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)O(CH₂)_(r),(CH₂)_(r)NR³C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r),(CH₂)_(r)SO₂NR³(CH₂)_(r), (CH₂)_(r)NR³SO₂(CH₂)_(r), and(CH₂)_(r)NR³SO₂NR³(CH₂)_(r); R^(1a) and R^(1b) are independently H orselected from —(CH₂)_(r)—R^(1′), —CH═CH—R^(1′), NHCH₂R^(1″), OCH₂R^(1″),SCH₂R^(1″), NH(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′); R^(1′) is selected from H, C₁₋₃ alkyl, F, Cl,Br, I, —CN, —CHO, (CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c),OC(O)R², (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR²,C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a),OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a),NR²SO₂R^(2b), C₃₋₆ carbocyclic group substituted with 0–2 R⁴, and 5–10membered heterocyclic system containing from 1–4 heteroatoms selectedfrom the group consisting of N, O, and S substituted with 0–2 R⁴; R^(1″)is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a), S(O)R^(2b),S(O)₂R^(2b), and SO₂NR²R^(2a); R², at each occurrence, is selected fromH, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic group substituted with 0–2R^(4b), and 5–6 membered heterocyclic system containing from 1–4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0–2 R^(4b); R^(2a), at each occurrence, is selectedfrom H, CF₃, C₁₋₆ alkyl, benzyl, phenethyl, C₃₋₆ carbocyclic groupsubstituted with 0–2 R^(4b), and 5–6 membered heterocyclic systemcontaining from 1–4 heteroatoms selected from the group consisting of N,O, and S substituted with 0–2 R^(4b); R^(2b), at each occurrence, isselected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclicgroup substituted with 0–2 R^(4b), and 5–6 membered heterocyclic systemcontaining from 1–4 heteroatoms selected from the group consisting of N,O, and S substituted with 0–2 R^(4b); R^(2c), at each occurrence, isselected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclicgroup substituted with 0–2 R^(4b), and 5–6 membered heterocyclic systemcontaining from 1–4 heteroatoms selected from the group consisting of N,O, and S substituted with 0–2 R^(4b); R³, at each occurrence, isselected from H, C₁₋₄ alkyl, and phenyl; R^(3a), at each occurrence, isselected from H, C₁₋₄ alkyl, and phenyl; R^(3c), at each occurrence, isselected from C₁₋₄ alkyl, and phenyl; A is C₃₋₁₀ carbocyclic groupsubstituted with 0–2 R⁴; B is Y; Y is 5–10 membered heterocyclic systemcontaining from 1–4 heteroatoms selected from the group consisting of N,O, and S substituted with 0–2 R^(4a); R⁴, at each occurrence, isselected from H, ═O, (CH₂)_(r)OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a),NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a),NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃,NHCH₂R^(1″), OCH₂R^(1″), and SCH₂R^(1″); R^(4a), at each occurrence, isselected from H, ═O, (CH₂)_(r)OR², (CH₂)_(r)—F, (CH₂)_(r)—Br,(CH₂)_(r)—Cl, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a),(CH₂)_(r)NR²R^(2b), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a),NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl,C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃; R^(4b), ateach occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl, Br, I,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), NR³ C(O)R^(3a), C(O)NR³R^(3a), NR³ C(O)NR³R^(3a),C(═NR³)NR³R^(3a), NR³ C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃; R⁵, at each occurrence, isselected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0–2 R⁶, andbenzyl substituted with 0–2 R⁶; R⁶, at each occurrence, is selected fromH, OH, (CH₂)_(r)OR₂, F, Cl, Br, I, C₁₋₄ alkyl, CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a),and NR²SO₂C₁₋₄ alkyl; p is selected from 0, 1, and 2; r is selected from0, 1, 2, and 3; and, t is selected from 0 and
 1. 2. A compound accordingto claim 1, wherein: M is


3. A compound according to claim 1, wherein: D-E is3-aminobenzisoxazol-5-yl.
 4. A compound according to claim 1, wherein: Zis selected from (CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r)C(O)O(CH₂)_(r),(CH₂)_(r)C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r), and(CH₂)_(r)SO₂NR³(CH₂)_(r).
 5. A compound according to claim 1, wherein: Zis selected from (CH₂)_(r)C(O)(CH₂)_(r)and (CH₂)_(r)C(O)NR³(CH₂)_(r). 6.A compound according to claim 1, wherein: Z is(CH₂)_(r)C(O)NR³(CH₂)_(r).
 7. A compound according to claim 1, wherein:Z is C(O)NH.
 8. A compound according to claim 1, wherein: Y is selectedfrom one of the following carbocyclic and heterocyclic systems which aresubstituted with 0–2 R^(4a); phenyl, piperidinyl, piperazinyl, pyridyl,pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole,1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran,benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole,indazole, benzisoxazole, benzisothiazole, and isoindazole.
 9. A compoundaccording to claim 1, wherein: Y is selected from one of the followingcarbocyclic and heterocyclic systems which are substituted with 0–2R^(4a); phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl,oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole,1,2,4-triazole, 1,2,5-triazole, and 1,3,4-triazole.
 10. A compoundaccording to claim 1, wherein: Y is imidazolyl substituted with 0–2R^(4a).
 11. A compound according to claim 1, wherein: A is C₅₋₆carbocyclic group substituted with 0–2 R⁴; and, R⁴, at each occurrence,is selected from H, ═O, OR², CH₂OR², F, Cl, C₁₋₄ alkyl, NR²R^(2a),CH₂NR²R^(2a), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a),C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂—C₁₋₄alkyl, S(O)₂R⁵, an CF₃.
 12. A compound according to claim 1, wherein: Ais phenyl substituted with R⁴; and, R⁴ is F.
 13. A compound according toclaim 1, wherein: R^(1a) is —(CH₂)_(r)—R^(1′); and, R^(1′) is selectedfrom H, C₁₋₃ alkyl, F, Cl, Br, I, CF₃, (CH₂)_(r)OR², NR²R^(2a),C(O)R^(2c), S(O)_(p)R^(2b), and NR²SO₂R^(2b).
 14. A compound accordingto claim 1, wherein: R^(1a) is selected from H, C₁₋₃ alkyl, F, Cl, Br,CF₃, CH₂OR², C(O)R^(2c), S(O)_(p)R^(2b), and NR²SO₂R^(2b).
 15. Acompound according to claim 1, wherein: R^(1a) is CF₃.
 16. A compoundaccording to claim 1, wherein: R^(4a), at each occurrence, is selectedfrom H, ═O, (CH₂)_(r)OR², F, Cl, C₁₋₄ alkyl, NR²R^(2a), CH₂NR²R^(2a),NR²R^(2b), CH₂NR²R^(2b), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b),C(O)NR²R^(2a), C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), SO₂NR²R^(2a),S(O)₂R⁵, and CF₃.
 17. A compound according to claim 1, wherein: R^(4a),at each occurrence, is selected from CH₂OR² and CH₂NR²R^(2a).
 18. Acompound according to claim 1, wherein: R², at each occurrence, isselected from H and C₁₋₆ alkyl; R^(2a), at each occurrence, is selectedfrom H and C₁₋₆ alkyl; R^(2b), at each occurrence, is selected from C₁₋₄alkoxy and C₁₋₆ alkyl; and, R^(2c), at each occurrence, is selected fromOH, C₁₋₄ alkoxy, and C₁₋₆ alkyl.
 19. A compound according to claim 1,wherein: R², at each occurrence, is selected from H and CH₃; and,R^(2a), at each occurrence, is selected from H and CH₃.
 20. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 1 or a pharmaceutically acceptable salt thereof.
 21. A methodfor treating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof.